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Wenjun Ouyang,1 Sascha Rutz,1 Natasha K. Crellin,1
Patricia A. Valdez,3 and Sarah G. Hymowitz2
by University of Guelph on 05/31/12. For personal use only.

1
Department of Immunology, 2 Department of Structural Biology, Genentech, Inc.,
South San Francisco, California 94080; email: ouyang@gene.com
3
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Bethesda, Maryland 20892

Annu. Rev. Immunol. 2011. 29:71–109 Keywords

First published online as a Review in Advance on
December 13, 2010
The Annual Review of Immunology is online at
immunol.annualreviews.org
This article’s doi:
10.1146/annurev-immunol-031210-101312
Copyright  c 2011 by Annual Reviews.
All rights reserved
0732-0582/11/0423-0071$20.00
psoriasis, IBD, infectious diseases, autoimmune diseases, Th17
Abstract
The IL-10 family of cytokines consists of nine members: IL-10,
IL-19, IL-20, IL-22, IL-24, IL-26, and the more distantly related
IL-28A, IL-28B, and IL-29. Evolutionarily, IL-10 family cytokines
emerged before the adaptive immune response. These cytokines elicit
diverse host defense mechanisms, especially from epithelial cells, during
various infections. IL-10 family cytokines are essential for maintaining
the integrity and homeostasis of tissue epithelial layers. Members of this
family can promote innate immune responses from tissue epithelia to
limit the damage caused by viral and bacterial infections. These cy-
tokines can also facilitate the tissue-healing process in injuries caused
by infection or inflammation. Finally, IL-10 itself can repress proin-
flammatory responses and limit unnecessary tissue disruptions caused
by inflammation. Thus, IL-10 family cytokines have indispensable func-
tions in many infectious and inflammatory diseases.

71
 IY29CH04-Ouyang ARI 4 February 2011 15:27

INTRODUCTION

Antibacterial responses,
The interleukin (IL)-10 family of cytokines and

Key functions

tissue remodeling,
Immune repression

Antiviral responses
the closely related interferon (IFN) family of

wound healing
cytokines form the larger Class II cytokine fam-
ily (1, 2). Class II family cytokines were origi-
nally defined by virtue of their interactions with
Class II cytokine receptors. Overall, Class I and
Class II cytokine receptors share a similar ex-

Cellular targets
tracellular architecture consisting of tandem re-

Epithelial cells,
Epithelial cells
peats of Ig-like domains. Class II receptors can

leukocytes?
Leukocytes
be differentiated from Class I receptors on the
basis of sequence analysis. For instance, Class
II cytokine receptors lack the canonical Trp-
Annu. Rev. Immunol. 2011.29:71-109. Downloaded from www.annualreviews.org

Ser-X-Trp-Ser motif found in the extracellular

T cells, NK cells, NKT cells,

domain of the Class I receptors and differ in the

Myeloid cells, epithelial cells

Myeloid cells, epithelial cells
Myeloid cells, epithelial cells
Major cellular sources

Leukocytes, epithelial cells

number and spacing of their cysteine residues.
by University of Guelph on 05/31/12. For personal use only.

The cognate ligands for the Class II receptors

are thus referred to as the Class II cytokines.
IL-10 family cytokines can be further

Leukocytes
subgrouped in different ways based on their

Th2 cells

LTi cells
structure, genomic location, receptor usage,
and common downstream biological functions
(Table 1). In this review, for the convenience
of discussion, we categorize IL-10 family
β chain
IL-10R2
IL-20R2

IL-10R2
cytokines into three subgroups based primarily
on their biological functions. The first group
contains only IL-10 itself. IL-10 targets vari-
Receptor

ous leukocytes and mainly represses excessive

IL-20R1/IL-22R

inflammatory responses. The second group,

α chain

namely IL-20 subfamily cytokines, is composed

IL-10R1
IL-20R1

of IL-19, IL-20, IL-22, IL-24, and IL-26 (3). IL-20R1

IL-22R

This group of cytokines primarily acts on IL-28R

various epithelial cells and protects these
cells from invasion by extracellular pathogens
Structure

Monomer
Monomer
Monomer

Monomer

Monomer
Monomer
Monomer
such as bacteria and yeast. In addition, IL-20
Dimer?
Dimer

subfamily cytokines enhance tissue remodeling

and wound-healing activities, which help to
maintain tissue integrity and restore home-
Table 1 IL-10 family cytokines

location (human)

ostasis of epithelial layers during infection and

Chromosome

inflammatory responses. Finally, the last group

is the type III IFN group (or IFN λs), which
contains the closely related cytokines IL-28A,
12q16

19q13
1q32

IL-28B, and IL-29 (4). These cytokines induce

antiviral responses similar to those of type I
IFNs but primarily act on epithelial cells (5).
Moreover, these cytokines can synergize with
IL-28A
IL-28B
Name
IL-10
IL-19
IL-20
IL-24

IL-22

IL-26

IL-29

type I IFNs to boost host antiviral response.

72 Ouyang et al.
 IY29CH04-Ouyang ARI 4 February 2011 15:27
One of the central functional themes of IL-
10 family cytokines is their role in tissue protec-
tion. On the one hand, these cytokines prevent
excessive tissue damage caused by bacterial and
viral infections as well as proinflammatory re-
sponses. On the other hand, uncontrolled tissue
repair processes, such as the wound-healing re-
sponses triggered by IL-20 subfamily cytokines,
can result in diseases, such as psoriasis. This re-
view integrates recent data on the function and
regulation of IL-10 family cytokines during in-
fectious and inflammatory diseases.
Annu. Rev. Immunol. 2011.29:71-109. Downloaded from www.annualreviews.org
IL-10 FAMILY CYTOKINES
AND THEIR RECEPTORS
IL-10, which was identified by Mosmann and
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colleagues (6) in 1989, is the founding mem-
ber of this family of cytokines. Initially, the
IL-10 protein was described as a secreted cy-
tokine synthesis inhibitory factor (CSIF) from
Th2 clones because it inhibits the production
of several cytokines, such as IFN-γ, from Th1
cells (6). The human and mouse CSIF cDNA
was subsequently cloned and renamed IL-10 (7,
8). Mature human and mouse IL-10 has 160
amino acids and forms noncovalently linked ho-
modimers. IL-10 binds to two receptor chains,
IL-10R1 and IL-10R2. The IL-10R1 receptors
in mouse and human were identified by expres-
sion cloning in 1993 based on their affinity for
Flag-tagged-rIL-10 (9, 10). IL-10R1 is struc-
turally similar to IFNR. When human IL-10R1
was overexpressed in hamster cells (COS-1), it
failed to establish the responsiveness of these
cells to human IL-10, suggesting that another
receptor chain was required for the function of
IL-10 (11). Expression of both IL-10R1 and
CRF2-4 (12), a previously cloned Class II cy-
tokine receptor member, restored the signal-
ing of IL-10 (11). CRF2-4 was therefore re-
named IL-10R2. The functional importance of
IL-10R2 was further confirmed by the obser-
vation that macrophages and splenocytes from
IL-10R2-deficient mice were unresponsive to
stimulation by IL-10 (13).
Il19, Il20, and Il24 are closely linked
to Il10 on human chromosome 1q32 (14).
All three genes also share similar genomic
structures with Il10, composed of five exons
and four introns. Il24, initially referred to as
melanoma differentiation-associated cDNA-7
(MDA-7), was the first Il10 homologous gene
discovered in 1995 (15). The human genome
project dramatically facilitated the discovery of
novel cytokines. Il19 and Il20 were identified
through the mining of the EST database for
Il10 homolog genes (16, 17). IL-19, IL-20, and
IL-24 bind to a common two-chain receptor
complex that consists of IL-20R1 and IL-20R2
chains (17–20). In addition, IL-20R2 can also
pair with IL-22R to form a heterodimeric
receptor complex that is preferentially used by
IL-20 and IL-24, but not by IL-19 (18–20).
The genes for IL-22 and IL-26 are not
colocalized with Il10. Instead, they are located
near the Ifng gene on human chromosome
12q16. Il22 was originally cloned from a
mouse T cell line treated with IL-9 and
named IL-10-related T cell–derived inducible
factor (IL-TIF) (21). In contrast, Il26 was
initially identified as AK155 by subtractive
hybridization from human T lymphocytes
infected with Herpesvirus saimiri (HVS) (22).
IL-22 and IL-26 share the common β chain
receptor, IL-10R2, with IL-10. However,
each of the cytokines binds to its unique α
chain receptor, namely IL-22R (also called
IL-22RA1) and IL-20R1, for IL-22 and IL-26,
respectively (23–25). In addition, a secreted
IL-22R homolog, IL-22BP or IL-22RA2, has
been identified. IL-22BP shows 33% amino
acid sequence identity with the extracellular
domain of IL-22R. IL-22BP binds to IL-22
with high affinity and neutralizes its activity in
vitro (26–28). In certain mouse strains, such as
C57Bl/6, FVB, and 129, a duplication of the
Il22 locus has occurred (29). The second copy
of Il22, namely Il22b, is highly homologous to
Il22 at the DNA level. However, currently no
evidence supports that this copy of Il22b is tran-
scribed or has a function in vivo. Interestingly,
the Il26 gene locus is deleted in mice, although
it is maintained through evolution in many
other animals, such as dog, frog, and zebrafish
(30).
www.annualreviews.org • IL-10 Family Cytokines in Immunity 73
 IY29CH04-Ouyang ARI 4 February 2011 15:27

Il28A, Il28B, and Il29 (also called IFN-λ2,

IFN-λ3, and IFN-λ1, respectively) were iden-
a b tified through genomic mining for novel genes
D similar to the genes for IFN and the IL-10
D E B’ family of cytokines (31, 32). These three genes
A A F C
F were later classified as type III IFNs (or the
B
F’ C C’ IFN λ family) because of their functional sim-
B A’ E
D’ ilarities to type I IFNs (4). As is the case with
E’
type I IFNs, IL-28A, IL-28B, and IL-29 are all
readily induced from human peripheral blood
c mononuclear cells (PBMCs) upon stimulation
Proposed IL-10R2 with poly(I:C) or encephalomyocarditis virus
binding site
(EMCV). Similar mechanisms for the induc-
tion of type I IFNs, such as RIG-I, IPS-1,
Annu. Rev. Immunol. 2011.29:71-109. Downloaded from www.annualreviews.org

D2
E B’ TBK1, and IFN regulatory factor 3 (IRF3), are
D
F D1
also used by type III IFNs during viral infec-
A C’
tions (33). Moreover, IL-28 and IL-29 also in-
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F’ C
D1 B A’ duce similar downstream biological effects as
D’
D2 type I IFNs (31). Structurally, however, type
E’
III IFNs are more closely related to IL-10
Proposed IL-10R2 family cytokines, especially IL-22 (34). Indeed,
binding site
IL-28A, IL-28B, and IL-29 also signal through
d the same IL-10R2 chain, paired with their
Proposed IL-10R2
binding site unique IL-28R as the α chain (31, 32). Inter-
estingly, type III IFNs seem to preferentially
target epithelial cells (35, 36). It has been pro-
D2 D
posed, therefore, that type III IFNs and IL-20
A F C subfamily members have parallel functions in
B the protection of epithelial tissue against viral
E
and bacterial infections, respectively (34).
D1

STRUCTURE AND
Figure 1 DOWNSTREAM
Structure of IL-10 family cytokines and receptor complexes. (a) Crystal SIGNALING PATHWAYS
structure of IL-10 from the IL-10/IL-10R1 complex (pdb 1Y6K). IL-10 Because of their biological importance, the
protomers are depicted with helices rendered as cylinders. Helices are labeled.
(b) Crystal structure of monomeric IL-22 from the IL-22/IL-22R1 complex
structure and function of the IL-10 family of
(pdb code 3DGC). Helices are shown as in (a) and colored by gradient from N cytokines has been extensively studied (1, 37,
terminus (dark blue) to C terminus (cyan). In the monomeric cytokines, the loop 38). Rather than reiterate the detailed charac-
connecting the D and E helices is folded so that the E and F helices complete terization of previous reviews, the present work
the monomer core. (c) Complex of IL-10R1 bound to IL-10 (pdb code 1YK6). briefly summarizes the key structural features of
IL-10 is colored as in (a). IL-10R1 ( yellow, green) is depicted with beta strands
rendered as arrows. The N-terminal D1 and C-terminal D2 domains are
these ligands (Figure 1). All members of the
labeled. Based on the work of Yoon et al. (52), the investigators propose that IL-10 family of Class II cytokines possess a
IL-10R2 binds adjacent to IL-10R1 and interacts with the AD face of the characteristic α-helical fold consisting of six he-
cytokine. (d ) Complex of IL-22R1 bound to IL-22. IL-22 is colored as in (a), lices labeled A to F and connecting loops. The
IL-22R1 is colored and labeled analogously to IL-10R1 in (c). The proposed structural core of the monomeric ligands is a
IL-10R2-binding site is labeled.
compact four-helix bundle composed of helices
A, C, D, and F. Helix B tends to be much shorter

74 Ouyang et al.
 IY29CH04-Ouyang ARI 4 February 2011 15:27
than the other helices and packs against the N-
terminal portion of helix C. Helix E binds to
the periphery of the bundle interacting primar-
ily with helices B, C, and the A–B connecting
loop. Despite possessing a common fold, fam-
ily members are divergent at the sequence level;
for instance, IL-22 and IL-10 share only 22%
sequence identity.
The important structural distinction within
the family is between the domain-swapped
dimers exemplified by IL-10 (and viral or-
thologs) and likely by IL-26 and the monomeric
family members such as IL-19, IL-20, IL-22,
IL-24, and the IL-28s (IFN λs) (Figure 1a,b).
Annu. Rev. Immunol. 2011.29:71-109. Downloaded from www.annualreviews.org
The distinctive intertwined dimer interaction
was first revealed by the structure of IFN-γ
(39). Subsequent structural studies of IL-10
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(40, 41) showed that it also forms a domain-
swapped dimer in which two adjacent peptide
chains exchange helices E and F to form a
twofold symmetric, reciprocal dimer. The
addition of six amino acids to the DE loop
results in a functional IL-10 that behaves as
a monomer in solution, indicating that the
ability to form a domain-swapped dimer is
modulated, at least in part, by loop length and
conformation (42). Intriguingly, IL-22 has
been reported to form higher-order species
including dimers and tetramers at high protein
concentration. Notably, molecular envelopes
determined by small-angle X-ray scattering
indicate that the overall shape of these IL-22
dimers is remarkably similar to that of the
intertwined IL-10 dimer (43). Although the
biological importance of this phenomenon has
not been determined, investigators postulate
that differences in stoichiometry depending
on protein concentration may affect signaling.
Despite this solution behavior, crystal struc-
tures of IL-22 either alone (44) or bound to
IL-22R1 (45) do not show any evidence of
domain-swapped dimer formation.
The basic paradigm of Class II cytokine
receptor-ligand interaction was revealed by the
structure of IFN-γ bound to its high-affinity
receptor in 1995 (46) and was confirmed by
structure of the IL-10-IL-10R1 (47), IL-22-IL-
22R1 (45, 48), and IL-22-IL-22BP complexes
(49) (Figure 1c,d ). These structures showed
that both the extracellular domain of the re-
ceptor and the receptor binding mode are sim-
ilar to that of Class I cytokines and receptors
as exemplified by the growth hormone–growth
hormone receptor interaction (50), despite the
differences in sequence and stoichiometry. Like
Class I receptors, Class II receptors consist
of tandem β-sheet rich Ig-like domains with
Fibronectin type III connectivity. Intrastrand
loops contributed by both domains as well as
the short interdomain linker form an elbow-like
ligand-binding surface. The receptor-ligand
binding mode is essentially identical for ei-
ther dimeric (IL-10 or IFN-γ) or monomeric
(IL-22) cytokines. In both cases, the receptor
binds to the surface formed by the helices A
and F and the AB loop.
Recent studies of the structure of the low-
affinity IL-10R2 receptor confirm that it pos-
sesses a similar molecular architecture despite
binding several orders of magnitude more
weakly to cognate cytokines than do the respec-
tive high-affinity receptors (51). Yoon, Walter,
and coworkers (52) used a combination of mu-
tagenesis and computational docking to suggest
that IL-10R2 likely binds to helices A and D on
its cognate ligands adjacent to the high-affinity
interaction site. This proposal is consistent with
what has been seen more broadly for cytokine-
receptor interactions (for a recent review, see
53).
IL-10 family cytokines activate the Jak-
STAT signaling pathway (Figure 2). STAT3
is the key downstream transcription factor
used by IL-10 and IL-20 subfamily cytokines,
whereas the ISGF3 (IFN-stimulated gene fac-
tor 3) complex is induced by type III IFNs (31)
(Figure 2). Jak1 and Tyk2 are associated with
IL-10R1 and IL-10R2, respectively (54, 55).
IL-10 activates STAT1, STAT3, and some-
times STAT5. STAT3, but not STAT1, is crit-
ical in mediating the function of IL-10 in im-
mune cells (56, 57) (Figure 2). The suppressive
effects of IL-10 on the production of proinflam-
matory cytokines are completely abolished in
macrophages and neutrophils lacking STAT3
(57).
www.annualreviews.org • IL-10 Family Cytokines in Immunity 75
 IY29CH04-Ouyang ARI 4 February 2011 15:27

IL-10 IL-22 IL-28

IL-10R1 IL-10R2 IL-22R IL-10R2 IL-28R IL-10R2

Jak1 Tyk2 Jak1 Tyk2 Jak1 Tyk2

Y Y
Y STAT2
Y ?
Y
Y

Y
STAT1
MEK
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IRF9
ERK JNK p38
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ISGF3
STAT1 STAT3 STAT5 STAT1 STAT5 STAT3

NUCLEUS

Figure 2
Receptors and downstream signaling of IL-10, IL-22, and IL-28. IL-10 family cytokines primarily activate Jak/STAT pathways upon
binding to their functional receptors. IL-10 and IL-22 mainly signal through STAT3. IL-22R can associate with STAT3 in a
tyrosine-independent manner. IL-28 and IL-29 activate the ISGF3 (IFN-stimulated gene factor 3) complex.

IL-20 subfamily cytokines also activate
STAT3. Among this group of cytokines, the
downstream signaling pathway of IL-22 is cur-
rently the most well understood (Figure 2). As
is the case for IL-10, IL-22 induces activation
of the Jak/STAT pathway upon binding to
the IL-22R/IL-10R2 heterodimeric receptor
complex. Jak1 and Tyk2, but not Jak2, are phos-
phorylated upon IL-22 binding (58). IL-22
stimulation can activate three STAT molecules,
including STAT1, STAT3, and STAT5 (23,
58). There are in total eight tyrosine residues in
the intracellular domain of IL-22R (59). Inter-
estingly, although these tyrosine residues are
required for the recruitment and activation of
STAT1 and STAT5 upon IL-22 stimulation,
they are dispensable for STAT3 activation.
IL-22R can use a novel mechanism to consti-
tutively bind to STAT3 through its C-terminal
tail interacting with the coiled-coil domain
of STAT3 (59). In addition to the Jak/STAT
pathway, IL-22 can also activate ERK, JNK,
and p38 MAP kinase pathways in a rat hepatoma
cell line, H4IIE, and in a human intestinal
epithelial cell line, HT29 (58, 60). Further-
more, AKT phosphorylation is reported upon
IL-22 treatment in H4IIE, HT29, and murine
hepatocytes (58, 60, 61). However, in a murine
breast cancer cell line, EMT6, IL-22 seemed
to promote a cell cycle arrest through the in-
hibition of ERK1/2 and AKT phosphorylation
(62).

76 Ouyang et al.
 IY29CH04-Ouyang ARI 4 February 2011 15:27
CELLULAR SOURCES AND
REGULATION OF IL-10
FAMILY CYTOKINES
IL-10 family cytokines are produced by various
leukocytes. Tissue epithelial cells can also
secrete some of these cytokines. IL-10 and
IL-22 are the most well studied among the
family members in terms of their regulation.
IL-10 is expressed by cells of the innate and the
adaptive immune system, including dendritic
cells (DCs), macrophages, mast cells, natural
killer (NK) cells, eosinophils, neutrophils,
CD4 and CD8 T cells, and B cells (reviewed
Annu. Rev. Immunol. 2011.29:71-109. Downloaded from www.annualreviews.org
in 2, 63–69). Similarly, IL-22 is produced by
various leukocytes, such as CD4, CD8, γδ T
cells, NK cells, DCs, and various lymphoid
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tissue inducer (LTi)-like subsets (70–75).
Consistent with their different functional roles
in inflammation, the regulation of these two
cytokines is drastically different.
IL-19, IL-20, and IL-24 are primarily gen-
erated by myeloid cells (76). T cells and ep-
ithelial cells can secrete some of these cytokines
upon certain stimulations. IL-28A, IL-28B, and
IL-29 can be produced by leukocytes (5, 31, 32).
The induction of these type III IFNs is report-
edly similar to that of type I IFNs; however,
detailed analysis of the regulation in individ-
ual cell types is still lacking. The regulation of
IL-26 awaits further characterization. Existing
data suggest that in humans the expression pat-
terns of IL-26 are similar to those of IL-22, con-
sistent with the linkage of these two cytokines
in the genome (77–79).
The Production and Regulation of
IL-10 Family Cytokines in T Cells
T cells are one of the sources of IL-10, IL-22,
IL-24, and IL-26. IL-10 can be produced by
virtually all T cell subsets, including Th1, Th2,
Th9, and Th17 effector T cells, regulatory T
cells, and CD8+ T cells (reviewed in 2, 63–69).
IL-22 is produced by Th1, Th17, γδ T cells,
and CD8 T cells. However, Th2, Th9, regula-
tory T cells, and B cells have not been reported
to produce significant amounts of IL-22. So far,
Th2 cells are likely the main source of IL-24 in
T cells, while the expression of IL-26 follows
IL-22 in most examined cases in the human
system (77–79).
IL-10 in regulatory T cells. Regulatory T
cells constitute a largely heterogeneous pop-
ulation of cells that can be defined based on
their potential to suppress other immune cells
and thereby limit or suppress immune re-
sponses. Among IL-10 family members, IL-10
is the only cytokine produced by these cells
and is required for their function. The best-
characterized subset of regulatory T cells is the
FoxP3+ Treg that originates from the thymus.
These cells usually do not express IL-10 upon
restimulation ex vivo (80, 81) unless they are
isolated from the gut (82). The role of IL-10
for the suppressive function of Tregs has been
extensively reviewed elsewhere (65, 67, 83–86).
However, the signals triggering IL-10 produc-
tion in Tregs are not well defined. IL-2 and
IL-4 induce IL-10 production in Tregs in vitro
(87, 88). The signals required for IL-10 expres-
sion in vivo remain elusive, although TGF-β is
required (82).
Various antigen-induced T cell populations
with suppressive capacities have been described
(reviewed in 65, 83, 89, 90). These cells were de-
fined as regulatory T cells based on either their
expression of FoxP3 or their production of reg-
ulatory cytokines, such as IL-10, in the absence
of classical effector cytokines. IL-10-producing
Tr1 cells were originally generated by repeated
in vitro stimulation of T cells in the presence of
IL-10 (91). Treatment with immunosuppres-
sive drugs, such as the combination of vitamin
D3 and dexamethasone, has been shown to in-
duce Tr1 cells (92). In vivo TGF-β, but not
IL-10, is required for the development of IL-
10-competent regulatory T cells (82).
Th2 cells produce IL-10 and IL-24. IL-10
production was first described in Th2 cells (6,
7). In these cells, IL-10 is coexpressed with
other Th2 cytokines IL-4, IL-5, and IL-13 and
is regulated by Th2-associated signaling path-
ways and transcription factors, including IL-4,
www.annualreviews.org • IL-10 Family Cytokines in Immunity 77
 IY29CH04-Ouyang
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ARI 4 February 2011 15:27
STAT6, and GATA3 (93–95). Recently, stud-
ies demonstrated that IL-27, a member of the
IL-12 cytokine family that by itself promotes
Th1 differentiation, enhances IL-10 produc-
tion in Th2 cells in a STAT1- and STAT3-
dependent manner (96). A Th2-related subset,
Th9, has been described in mouse and human
(97–99). Th9 cells are generated in the pres-
ence of IL-4 and TGF-β and produce IL-9 as a
signature cytokine. Th9 cells can produce high
levels of IL-10 (97–99) but seem to lack sup-
pressive potential (98). The regulation of IL-10
expression in these cells is presently unknown.
Unlike IL-10, which is essentially produced
by all Th subsets, IL-24 is preferentially pro-
duced by Th2 cells (100). IL-24 lacks immune
repressive functions, and its detailed regulation
in Th2 cells is currently unclear.
Regulation of IL-10 and IL-22 in Th1 and
Th17 cells. Shortly after the initial descrip-
tion of IL-10 as a Th2 cytokine, studies found
that it is produced by human Th1 cells as well
(101, 102). Th1 cells require strong activation
and the presence of IL-12 in order to coex-
press IFN-γ and IL-10 (95, 103–105). As in
Th2 cells, IL-27 also induces IL-10 production
in Th1 cells in mouse (96, 106–109) and human
(110). TGF-β acts synergistically with IL-27 in
inducing IL-10 (96, 111).
Several groups have recently shown that
Th17 cells produce IL-10 (96, 105, 106, 112).
The cytokine combination of TGF-β and IL-6,
besides potently inducing Th17 differentiation
and IL-17 expression, induces IL-10 produc-
tion in Th17 cells (Figure 3) (112). In contrast,
IL-23 is required for the long-term in vivo func-
tion of Th17 cells but inhibits IL-10 production
from these cells (112). In addition, the combi-
nation of IL-27 and IL-6 is a strong inducer of
IL-10 in Th17 cells (96), whereas IL-27 alone
largely suppresses IL-17 production while in-
ducing IL-10 (110).
Th1 cells were originally identified as the
source of IL-22 as well (113). Few data exist
on the detailed regulation of IL-22 from Th1
cells. Presumably, IL-12 is required for the in-
duction of IL-22. We have also noticed that IL-
78 Ouyang et al.
18 can further enhance IL-22 production from
Th1 cells (M. Munoz, Y. Zheng, K. Wong, C.
Loddenkemper, M. Heimesaat, O. Liesenfeld,
and W. Ouyang, manuscript in preparation).
IL-22 is one of the signature cytokines, be-
sides IL-17 and IL-21, that are preferentially
produced by Th17 cells (114–116). Although
IL-6 and TGF-β are indispensable for de novo
differentiation of murine Th17 cells (117–119),
IL-6 alone is sufficient to induce IL-22 from
naive T cells in vitro in mouse and human (116,
120). However, IL-6 is not essential for IL-22
induction in vivo, at least in Concanavalin A
(ConA)-induced hepatitis and Citrobacter roden-
tium infection models (61, 121), whereas IL-
6 is required for maximal IL-17 production
(121). Interestingly, IL-21 was found to pro-
mote IL-22 expression comparable to IL-6 in
vitro (122), suggesting that IL-21 and IL-6 may
have a redundant role. In combination with tu-
mor necrosis factor (TNF)-α, IL-6 is particu-
larly effective in promoting the differentiation
of a recently identified population of human
Th22 cells (120) that produces IL-22 but not
IL-17.
IL-23, although not sufficient to induce de
novo IL-17 production from naive T cells (112,
117, 118), is essential in promoting IL-22 pro-
duction from many immune cell types. IL-23
alone induces IL-22 production from CD4+
and CD8+ T cells, γδ T cells, monocytes,
CD11c+ DCs, and LTi cells (70, 74, 112, 116).
In vivo, IL-22 induction is significantly com-
promised in IL-23-deficient mice under various
immune challenges (122, 123–126).
Finally, the roles of TGF-β in the regulation
of IL-17 and IL-22 production are strikingly
different. TGF-β is required for robust IL-17
and IL-10 induction in naive T cells (117–119)
(Figure 3). In contrast, not only is TGF-β
not required for the induction of IL-22 expres-
sion, but it also potently inhibits IL-22 expres-
sion in murine Th17 cells in a concentration-
dependent manner (116). TGF-β completely
blocks IL-22 induction in human Th22 cells
generated by IL-6/TNF treatment (120). The
molecular basis for this suppressive effect is cur-
rently unknown.
 IY29CH04-Ouyang ARI 4 February 2011 15:27

IL-10 regulation IL-22 regulation

Dll-4 Dll-4
Notch Notch
receptor receptor
IL-12 IL-27 IL-21 IL-6 IL-4 TGF-β TGF-β IL-6 IL-23 IL-21
AhR
ligand
IL-12R IL-27R IL-21R IL-6R IL-4R TGF-βR TGF-βR IL-6R IL-23R IL-21R

AhR
HSP90
NICD ? NICD
STAT1

STAT1

STAT3

STAT3

STAT6

STAT6

STAT3

STAT3
STAT4

STAT4
Annu. Rev. Immunol. 2011.29:71-109. Downloaded from www.annualreviews.org

CYTOSOL

NUCLEUS
?
by University of Guelph on 05/31/12. For personal use only.

? ? ?

STAT3

STAT3
?
STAT
STAT

MAML RBP-Jκ GATA3 c-Maf ARNT AhR MAML RBP-Jκ RORα RORγt BATF

IL-10 IL-22

Figure 3
Regulation of IL-10 and IL-22 in T cells. The expression of IL-10 and IL-22 is controlled by both common and distinct transcription
factors. STAT3 and Notch were shown to be involved in the transcriptional regulation of both cytokines. STAT3 activation by IL-27,
either alone or in combination with IL-6, or by TGF-β plus IL-6, promotes IL-10 production. Activated by IL-23, IL-6, and IL-21,
STAT3 is also crucial for IL-22 expression. Triggering of Notch by Dll-4 induces IL-10 expression in Th1 cells in synergy with
STAT4. Notch also induces IL-22 production in Th17 cells, possibly by activating AhR. Other factors, such as AhR, RORγt/RORα,
and BATF, control IL-22 production but are not involved in IL-10 regulation, whereas c-MAF and GATA3 control only IL-10
expression. (Dashed lines indicate transcriptional induction of the respective factor. Question marks indicate that the proposed binding
to the IL-10 or IL-22 promoter has not been demonstrated experimentally. Abbreviations: AhR, aryl hydrocarbon receptor; ARNT,
aryl hydrocarbon receptor nuclear translocator; BATF, basic leucine zipper transcription factor, ATF-like; Dll-4, Delta-like-4;
MAML, Masterlind-like; NICD, Notch intracellular domain; RBP-Jκ, recombining binding protein suppressor of hairless.)

Clearly, different cytokine networks are re- activation by IL-27, either alone or in com-
quired for the production of IL-10 and IL-22 bination with IL-6, or by TGF-β plus IL-6,
from Th1 and Th17 cells (Figure 3). Both com- promotes IL-10 production by Th1, Th2, and
mon and distinct transcription factors control Th17 cells in mouse and human (96, 106–108,
the production of these two cytokines in T cells. 110–112, 129).
STAT3 and Notch are two common transcrip- STAT3 is essential for the differentiation
tion factors that regulate IL-10 and IL-22 pro- of Th17 cells and for the expression of the
duction from Th1 and Th17 cells. Two puta- Th17 key transcription factors RORγt and
tive STAT-binding sites have been identified in RORα in response to TGF-β, IL-6, and IL-23
the murine and human IL-10 promoter (127, (130–132). Because all cytokines reported to
128). Generally, STATs are among the most induce IL-22 production, i.e., IL-23, IL-6,
universal and crucial transcriptional regulators and IL-21, signal through STAT3, it is not
of IL-10. STAT1, STAT3, and STAT4 have surprising that STAT3 is crucial for IL-22
all been linked to IL-10 regulation (103, 104, expression. Overexpression of a constitutively
106). Several reports demonstrate that STAT3 active STAT3 strongly enhances IL-23R and

www.annualreviews.org • IL-10 Family Cytokines in Immunity 79

 IY29CH04-Ouyang
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ARI 4 February 2011 15:27
IL-22 expression (133). STAT3-deficient T
cells are impaired in their expression of IL-22,
as well as of IL-17, IL-23R, and RORγt under
Th17-polarizing conditions in vitro (122, 133).
Activation of the Notch pathway via its lig-
and Delta-like-4 (Dll-4) promotes the coex-
pression of IL-10 and IFN-γ in Th1 cells
(134, 135). Furthermore, Notch strongly syn-
ergizes with IL-12 and IL-27 in the induc-
tion of IL-10 from Th1 cells (134). The
Notch pathway also promotes IL-10 produc-
tion from Th17 cells, although at a lower level
(S. Rutz and W. Ouyang, unpublished ob-
servation). The Notch pathway has recently
been implied in IL-22 regulation. Costimula-
tion of CD4+ T cells with either recombinant
Dll-4 (136) or antigen-presenting cells (APCs)
overexpressing Dll-1 (137) in the presence of
TGF-β/IL-6 or TGF-β/IL-6/IL-23 strongly
induces IL-22 production in vitro. More impor-
tantly, the Notch pathway also regulates IL-22
production in vivo. RBP-Jκ-deficient mice, in
which Notch signaling is blocked altogether,
are highly susceptible to the detrimental im-
munopathology associated with ConA-induced
hepatitis but could be protected by exogenous
IL-22 (137). Consistently, CD4+ T cells from
RBP-Jκ-deficient mice were largely impaired
in their ability to produce IL-22 through T cell
receptor–mediated stimulation (137).
Several other transcription factors regulate
the expression only of IL-10 and not of IL-22.
First, c-MAF belongs to the MAF family of
basic region and leucine zipper transcription
factors. Originally, c-MAF had been described
as a Th2 transcription factor directing the
expression of Il4 and thereby promoting Th2
differentiation (138, 139). Recently, c-MAF was
also implicated in the expression of IL-10 by
various T cell subsets (105, 108, 129). c-MAF
expression correlates with IL-10 production in
Th1, Th2, and Th17 cells and is dependent on
ERK activation in Th1 and Th17 cells (105). c-
MAF is synergistically upregulated by IL-6 plus
TGF-β or IL-27 plus TGF-β in Th17 cells,
and it is downstream of IL-27-induced IL-10
production in Th1 cells (108). c-MAF directly
induces IL-10 expression in T cells through
80 Ouyang et al.
binding to a MARE (MAF recognition element)
motif in the IL-10 promoter (129). Taken to-
gether, these findings are suggestive of c-MAF
as a universal transcriptional regulator of IL-10
expression in a wide range of immune cells.
Sp1 (140, 141), C/EBPs (142–144), IRF1
(127), activator protein-1 (AP-1) (145, 146),
NF-κB (147), and CREB (148) all reportedly
regulate IL-10 expression in myeloid cells and
T cells. AP-1 activity has been associated with
IL-10 production in T cells and macrophages.
An AP-1-specific binding motif has been
identified in the noncoding region that is
approximately 1 kb downstream of the IL-10
transcribed region (14, 149). This element
is responsible for JUN/AP-1-driven IL-10
production that is observed in Th2, but not
Th1, cells (14, 149). IL-10 production by T
effector cells also requires ERK activation (105,
150). In Th1 cells, IL-10 expression depends
on STAT4 and ERK. IL-21 and IL-27, both
potent inducers of IL-10 production in T cells
(see above), activate ERK (151, 152).
Different sets of transcription factors are
required for the production of IL-22 in T cells
(Figure 3). The retinoic acid–related orphan
nuclear receptor RORγt is necessary and
sufficient to drive Th17 development (153).
Its closely related family member, RORα, also
participates in the regulation of IL-17A and IL-
17F production in vitro and in vivo (132). Dou-
ble deficiencies in RORα and RORγt globally
impair Th17 generation and completely pro-
tect mice against experimental autoimmune
encephalomyelitis (EAE) (132). Interestingly,
most, but not all (120), cell types that produce
IL-22 express RORγt as well (72–74, 77, 132,
154–159). The exact involvement of RORγt
and RORα in the transcriptional regulation of
IL-22 is not well understood. RORα-deficient
T cells show normal IL-22 expression under
Th17 conditions in vitro, and forced expression
is not sufficient to induce IL-22 (132). Like-
wise, overexpression of RORγt alone is not
sufficient for IL-22 expression in murine (160)
or human T cells (78). RORγt-deficient cells,
however, show strongly reduced IL-22 expres-
sion in vitro in the presence of TGF-β/IL-6 or
 IY29CH04-Ouyang ARI 4 February 2011 15:27
TGF-β/IL-6/IL-23 (132) or TGF-β/IL-
21/IL-23 (122). Reduced IL-22 production is
observed in human Th22 cells after treatment
with a small interfering RNA against RORγt
(157). However, Duhen et al. (120) report that
human Th22 cells produce IL-22 while ex-
pressing low to undetectable levels of RORγt.
When considered together, these findings
suggest that RORγt acts in combination with
other pathways to regulate IL-22 expression.
Interestingly, only RORα/RORγt-double-
deficient T cells totally lack IL-22 expression
(132).
The cytosolic transcription factor aryl hy-
Annu. Rev. Immunol. 2011.29:71-109. Downloaded from www.annualreviews.org
drocarbon receptor (AhR) has been iden-
tified as a crucial factor in the develop-
ment of Th17 cells (160–163) and Tregs
by University of Guelph on 05/31/12. For personal use only.
(162). AhR was suggested as a link between
the adaptive immune system and environ-
mental factors because it recognizes numer-
ous small xenobiotic and natural molecules,
such as 2,3,7,8-tetrachlorodibenzo-p-dioxin
(TCDD) and the tryptophan photometabolite
6-formylindolo(3,2-b)carbazole (FICZ). Th17
cells express particularly high levels of AhR in
mouse and human (161, 162). AhR deficiency
impairs but does not prevent Th17 develop-
ment (161, 163). Interestingly, AhR is essential
for IL-22 expression in Th17 cells (160, 161),
γδ T cells (72), and human Th22 cells (120,
157). CD4+ T cells from AhR-deficient mice
can develop Th17 cell responses, but when con-
fronted with AhR ligand they fail to produce
IL-22 (161). Th17 cells from AhR-deficient
mice cannot produce IL-22 despite the pres-
ence of IL-23 under inflammatory conditions
such as immunization with CFA or injection
with heat-killed mycobacteria (161). The exact
mode of action of AhR remains elusive. The
core nucleotide sequence to which the nuclear
AhR complex binds, also termed the xenobi-
otic responsive element, occurs frequently in
the mammalian genome and is also represented
in Il17a, Il17f, Il22, and rorc. AhR is apparently
associated with other Th17-related factors to
activate Il22 transcription, given that, in AhR-
deficient T cells, forced expression of AhR un-
der neutral, Th1, or Th2 conditions does not
induce IL-22 even in the presence of its ligand
FICZ (160).
Other transcription factors that may reg-
ulate IL-22 production include basic leucine
zipper transcription factor, ATF-like (BATF),
IRF4, and IκBζ (Figure 3). BATF is a member
of the AP-1 superfamily of basic leucine zip-
per transcription factors. T cells from BATF-
deficient mice are completely impaired in their
differentiation into Th17 cells, and the mice are
resistant to EAE (164). BATF-deficient T cells
cannot express RORγt, RORα, AhR, IL-17A,
IL-17F, IL-21, or IL-22. IRF4 is crucial for
the development of Th17 cells (165, 166). It is
the only known Th17-related factor that is in-
duced in the absence of BATF. IRF4-deficient
T cells fail to upregulate RORγt or to pro-
duce IL-17 and IL-22 in response to a cocktail
of cytokines including IL-6 and TGF-β (165).
IκBζ, a nuclear IκB family member, has re-
cently been described as a transcription factor
required for Th17 development in mice. The
ectopic expression of IκBζ in naive CD4+ T
cells together with RORγt or RORα potently
induces Th17 development, even in the absence
of IL-6 and TGF-β. IL-22 expression upon
TGF-β/IL-6/IL-23 treatment is markedly re-
duced in IκBζ-deficient T cells (167). The ex-
pression of other Th17-associated transcrip-
tion factors, including RORα, RORγt, AhR,
IRF4, and BATF were found to be normal,
as was IL-6-induced STAT3 phosphorylation
(167).
Regulation of IL-10 Family Cytokines
in Myeloid Cells and Other Tissue
Cell Types
IL-10, IL-19, IL-20, and IL-24 are closely
linked in the genome. It is not surprising that
all these cytokines can be induced from myeloid
cells through TLR activation. IL-10 produc-
tion can be triggered in vitro in both DCs
(168–173) and macrophages (168, 174–176)
by stimulation with certain PRR ligands, e.g.,
Toll-like receptor (TLR) agonists. TLR2 lig-
ands appear to be particularly potent inducers
of IL-10 production by APCs, as demonstrated
www.annualreviews.org • IL-10 Family Cytokines in Immunity 81
 IY29CH04-Ouyang
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ARI 4 February 2011 15:27
with the synthetic TLR2 agonist Pam3cys
(170, 172) or by reduced IL-10 production
from macrophages during Candida albicans
infection in TLR2-deficient mice (177). TLR9
and TLR4 ligation also trigger IL-10 produc-
tion from macrophages and DCs (168, 178,
179). TLR-independent triggers of IL-10 pro-
duction include DC-SIGN (173) and Dectin-1
(171). The activation of CD40 reportedly
further enhances IL-10 production by DCs
(169, 171) and induces IL-10 in macrophages.
Myeloid cells are sources of IL-19, IL-20,
and IL-24 as well. Lipopolysaccharide (LPS)
stimulates the production of these three
cytokines from monocytes. Pretreatment
of monocytes with IL-4 and IL-13 further
increases the LPS-induced IL-19 production
(16). GM-CSF can also promote IL-19 expres-
sion from monocytes. TNF-α upregulates the
expression of IL-20 from human monocytes
(180). In psoriatic skin, IL-20 is mainly de-
tected in CD68+ /CD11C+ DCs. In addition
to myeloid cells and T cells, some tumor cells
such as melanoma cells also produce IL-24
(15). Epithelial cells are also a source for IL-19,
IL-20, and IL-24, and IL-20 expression from
keratinocytes can be induced by IL-22, IL-1β,
and ultraviolet B (3, 181–183). As discussed be-
low, the IL-20 subfamily cytokines produced by
myeloid cells and keratinocytes may participate
in the pathogenesis of psoriasis. Stimulation
with IL-17, IL-22, or IL-1β induces IL-19
from human bronchial epithelial cells, which
may play a role in host defense of bacterial
infections (124, 184). Finally, monocytes and
DCs produce low levels of IL-22 upon IL-23
stimulation (116, 121, 185, 186).
Expression of IL-22 in NK
and LTi-Like Subsets
The T cell compartment is not required for IL-
22-dependent protection in colitis models such
as C. rodentium infection (121, 187); therefore,
an IL-23-responsive cell belonging to the in-
nate compartment must also be a source of IL-
22. Initial reports identified IL-22-expressing
NK cells (188), which investigators suggested
82 Ouyang et al.
were involved in mediating protection from
colitis (187). Investigations into subsets of
NK cells conducted by several labs revealed a
population of cells that lacked lineage markers,
expressed NKp46, and were resident in mu-
cosal tissue such as gut lamina propria, Peyer’s
patches, and cryptopatches (77, 155, 159, 189).
These CD3− NKp46+ cells were all reported to
express RORγt, which is essential for the devel-
opment not only of Th17 cells, but also of LTi
cells. Although these CD3− NKp46+ RORγt+
cells express various markers associated
with NK cells, they express low levels of
IFN-γ and have low cytotoxic capacity but
produce high levels of IL-22 following stim-
ulation (77, 155, 159). Various names have
been proposed to describe IL-22-producing
NKp46+ RORγt+ cells, including NK22,
NKp46+ RORγt+ , and NCR22 (77, 190–192).
Murine NKp46+ RORγt+ cells were found to
contribute to resistance to C. rodentium, sug-
gesting a role in mucosal homeostasis (77, 154).
Murine and human LTi cells also produce
high levels of IL-22 upon activation (74, 75,
158). Human LTi cells have been identified
recently as a lin− CD45+ CD127+ RORC+
population (75). Human tonsil LTi cells
produce low levels of IFN-γ but high IL-22
following stimulation ex vivo. These cells are
NKp46+ , and activation of LTi cells from the
tonsil induces the expression of CD56; fetal
LTi cells acquire NK cell markers following
ex vivo culture with γc cytokines, suggesting
an intrinsic developmental link between LTi
cells and NKp46+ NK22 cells (75, 158)
(Figure 4). Recent publications suggest that
although similar in phenotype to conventional
NK cells, NKp46+ RORγt+ cells in human
and mouse comprise a cellular lineage that is
distinct from, yet developmentally related to,
conventional NK cells (158, 193) (Figure 4). In
a broader context, conventional NK cells, LTi
and LTi-like cells, and NKp46+ RORγt+ cells
may be considered part of a family of innate
lymphoid cells that mediate mucosal home-
ostasis. Recently, RORγt+ precursor cells have
been identified in fetal liver (194). These cells
can develop into both mature LTi cells and
 IY29CH04-Ouyang ARI 4 February 2011 15:27

IL-22

IL-7Rα IL-7Rα IFN-γ

NKp46 NKp46 NKp46
(human) NK1.1hi
CD4+/–
(mouse)
?
RORγt RORγt
Granzyme,
Perforin
C-Kit C-Kit
NKp44+ NKp44+, CD56+ CD56+
(human) (human) (human)
LTi, NK22, NCR22, NK cells
LTi-like NKp46+RORγt +
Annu. Rev. Immunol. 2011.29:71-109. Downloaded from www.annualreviews.org
by University of Guelph on 05/31/12. For personal use only.

Id2

Common
precursor?

Figure 4
LTi- and NK-like cells are major innate sources of IL-22. Human LTi cells and RORC+ NKp46+ NK22 cells can produce IL-22 upon
activation. These cells may share a common precursor during development.

NKp46+ RORγt+ cells, suggesting that they
may be a common precursor for the entire
family of innate IL-22-producing lymphocytes.
DIVERSE TARGET CELLS AND
BIOLOGICAL FUNCTIONS OF
IL-10 FAMILY CYTOKINES
IL-10 family cytokines target various cell types
in the body. Two β chains and four α
chains are used by these cytokines as receptors
(Table 1). The two β chains are relatively
broadly expressed, whereas the presence of the
α chain determines which cytokines a par-
ticular cell type responds to (70, 76). The
IL-10R2 chain is ubiquitously expressed,
whereas IL-20R2 expression is more limited
to various tissues enriched with epithelial cells,
such as skin and lung (17). A low level of
expression of IL-20R2 is also detected in
leukocytes. The IL-10R1 chain is mainly
expressed on leukocytes, whereas IL-22R1,
IL-20R1, and IL-28R1 are preferentially ex-
pressed on various tissue epithelial cells and
fibroblasts (9, 10, 17, 35, 36, 195). IL-10 is
thus the only family member primarily target-
ing leukocytes, while all other family members
preferentially regulate various other cell types,
especially epithelial cells, in the tissues.
IL-28A, IL-28B, and IL-29 induce down-
stream antiviral responses, similar to those
triggered by type I IFNs. Type III IFNs also
stimulate the expression of common IFN gene
signatures, such as Mx1 and Oas1 (31). Nearly
identical gene signatures are induced by type I
and type III IFNs from HepG2 and U266 cells
(196). Nevertheless, the antiviral and antipro-
liferative activities induced by IL-28 and IL-29
are different from those of IFN-α in terms
of potency and kinetics (197). The activities

www.annualreviews.org • IL-10 Family Cytokines in Immunity 83

 IY29CH04-Ouyang
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ARI 4 February 2011 15:27
induced by type III IFNs are in general weaker
than those induced by type I IFNs (31, 198).
Furthermore, in contrast to a broad spectrum
of cell types that respond to stimulation by
type I IFNs, only a few cell types, especially
epithelial cells, preferentially react to type III
IFNs (35, 36). IL-28A, IL-28B, and IL-29,
therefore, probably evolved to protect skin and
mucosal surfaces from viral invasion, which
is similar to the activities of IL-20 subfamily
cytokines in protection of epithelial layers
from bacterial infection.
IL-20 subfamily cytokines, except for IL-26,
share similar biological activities, especially on
keratinocytes, where all receptors for this group
of cytokines are expressed. IL-20 subfamily cy-
tokines induce broad biological functions that
are essential for epithelial integrity and innate
host defense (3, 60, 70, 199, 200). Interest-
ingly, although the receptor for IL-26 is also ex-
pressed on keratinocytes, IL-26 fails to induce
downstream effects similar to those induced by
other IL-20 subfamily cytokines in these cells
(3). However, it does activate STAT3 in colon
cells (25, 60). The reason for this observation is
unclear. It is still controversial whether IL-20
subfamily cytokines can function on leukocytes.
Neither IL-20R1 nor IL-22R has been detected
on leukocytes (76, 195). Reported activities of
this subgroup of cytokines on leukocytes range
from T cell activation and differentiation and
myeloid cell cytokine production to enhance-
ment of multipotential hematopoietic progeni-
tors (201–204). Further molecular characteriza-
tion of signal transduction pathways is required
to understand these biological activities. In ad-
dition, IL-24 reportedly exerts special antitu-
mor activity in numerous studies (reviewed in
205, 206). This antitumor activity is not shared
by IL-20 despite using the same receptor. The
antitumor activity requires overexpression of
intracellular IL-24 to induce endoplasmic retic-
ulum stress activities (205, 207). Therefore, it is
unclear whether this function reflects the natu-
ral biology of IL-24 as a cytokine.
Based on its protective activity in vivo and
its shared IL-10R2 chain with IL-10, IL-22
may have anti-inflammatory functions simi-
84 Ouyang et al.
lar to those of IL-10 (61, 187). However, in
contrast to IL-10, at a cellular level scarce
evidence supports a direct anti-inflammatory
function for IL-22 (3, 195, 208). Although
two studies observed that IL-22 induced IL-
10 production from a colon epithelial cell line,
Colo205 (77, 209), most expression-profiling
studies on IL-22 in various primary epithe-
lial cells demonstrate that IL-22 primarily pro-
motes innate inflammatory responses, tissue
protection, and wound-healing activities (3, 70,
195, 208). In addition, IL-22 does not induce
an anti-inflammatory response from leukocytes
because of the lack of IL-22R expression. Inter-
estingly, upon forced expression of IL-22R in
macrophages, IL-22 induces anti-inflammatory
functions in these cells similar to IL-10 (210).
Overexpressing IL-22R in lymphocytes in vivo,
however, results in systemic inflammation as
well as in neutrophilia (211). In conclusion, the
anti-inflammatory activity of IL-22 observed in
several models in vivo is probably mediated by
its indirect tissue protective activity.
IL-10 FAMILY CYTOKINES IN
HOST DEFENSE
Host defenses elicited by IL-10 family cy-
tokines are ancient mechanisms used by verte-
brates to protect against various infections (1, 2,
30). The key functions of the IL-10 family of cy-
tokines in host defense can be categorized into
three areas. First, IL-20 subfamily cytokines in-
duce innate defense mechanisms from epithe-
lial cells against extracellular pathogens, such as
bacteria and yeast. Second, type III IFNs pref-
erentially promote antiviral responses from ep-
ithelial cells and cooperate with type I IFNs in
the clearance of viral infections. Third, IL-20
subfamily cytokines and IL-10 prevent tissue
damage caused by infections and inflammation.
IL-20 subfamily cytokines stimulate epithelial
cell proliferation, antiapoptotic responses, and
tissue remodeling and healing. IL-10, on the
other hand, regulates and represses the expres-
sion of proinflammatory cytokines during the
recovery phase of infections and reduces the tis-
sue damage caused by these cytokines.
 IY29CH04-Ouyang ARI 4 February 2011 15:27
The functions of IL-10 in infections have
been recently reviewed (212, 213). IL-10 is a
general suppressive cytokine. It inhibits proin-
flammatory responses from innate and adaptive
immunity, and it prevents the lesions in tis-
sues caused by exacerbated adaptive immune re-
sponses. IL-10 is thus a central cytokine during
the resolution phase of inflammation. Consis-
tently, as is discussed below, blocking the IL-
10 pathway in mice causes spontaneous devel-
opment of inflammatory bowel disease (IBD).
However, evolutionarily pathogens have ex-
ploited the functions of IL-10 to repress the
normal host inflammatory responses during in-
Annu. Rev. Immunol. 2011.29:71-109. Downloaded from www.annualreviews.org
fections, thus establishing chronic infectious
states. Increased IL-10 expression has been as-
sociated with many chronic bacterial and viral
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infections. Furthermore, some viruses can pro-
duce their own version of IL-10 (vIL-10) to
directly suppress the immune responses of the
host (7). The induction of IL-10 in DCs and
macrophages represents a powerful mechanism
of immune evasion used by various pathogens.
Either IL-10 itself, or the subsequent induc-
tion of T regulatory cells, impairs pathogen
control and clearance in infection models with
lymphocytic choriomeningitis virus (LCMV)
(214), Schistosoma mansoni (215), Mycobacterium
tuberculosis (216), and Candida albicans (177).
Macrophage-derived IL-10 can inhibit the dif-
ferentiation of neighboring cells into classi-
cally activated macrophages, which allows the
macrophage population to be self-regulating
(217).
The secretion of IL-10 by Th1 cells repre-
sents a potent autoregulatory feedback loop that
protects against excessive inflammation and
potential tissue destruction during proinflam-
matory Th1-driven immune responses in infec-
tions. However, this mechanism is exploited by
pathogens to prevent their elimination, leading
to chronic infections (63, 64, 218). Although
IFN-γ/IL-10-secreting T cells had been rec-
ognized for many years, only recent studies dis-
covered that IFN-γ+ IL-10+ Tbet+ T cells are
indeed required in a Toxoplasma gondii infection
model to prevent excessive inflammation result-
ing in early mortality of the mice (219). Similar
results were obtained in a cutaneous Leishma-
nia major infection model. Here, IFN-γ+ IL-
10+ FoxP3− cells act to maintain a chronic, non-
resolving infection status. Upon adaptive trans-
fer, these IL-10-producing FoxP3− T cells,
but not IL-10-secreting FoxP3+ Tregs, can
interfere with pathogen clearance in L. major–
infected mice (82, 220). Blocking IL-10 has
thus been considered a therapeutic approach
for the treatment of certain chronic infections.
Unlike the anti-inflammatory functions of
IL-10, the rest of the cytokines in this family
enhance innate host defense mechanisms, es-
pecially from various tissues. Next, we focus on
IL-20 subfamily cytokines, especially IL-22, in
host defense against bacterial and yeast infec-
tions and the potential roles of type III IFNs
in viral infections. As discussed above, IL-20
subfamily cytokines induce various antimicro-
bial peptides from epithelial cells. These cy-
tokines probably exert similar and redundant
host defense functions during infections. At this
time, only IL-22 has been examined extensively
in vivo during bacterial infections. IL-24 has
been reported to modulate IFN-γ expression
in vitro and in vivo (221, 222). Administra-
tion of exogenous IL-24 protects the mice from
Salmonella typhimurium C5 infection. Although
IL-20 shares the same receptors as IL-24,
whether IL-20 has similar biological functions
is presently unclear. Elevated IL-22 has also
been detected in individuals who are resistant
to HIV-1 infection despite repeated exposure to
the virus (223). Furthermore, IL-22 is mapped
to the locus controlling Theiler’s virus–induced
encephalomyelitis (224). However, IL-22 does
not elicit direct antiviral responses from hepatic
cells, and most likely not from other epithelial
cells either (225). The in vivo role of IL-22, as
well as of other IL-20 subfamily cytokines, in
viral infections deserves more attention.
IL-22 in Bacterial Infections
An early effort examined the role of IL-22
during infection with Listeria monocytogenes,
a gram-positive intracellular bacterium, given
the function of IL-22 in liver protection (61).
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IL-22 is not required for either the innate or the
adaptive immune responses against L. monocyto-
genes. Because of the high expression of IL-22R
on mucosal epithelial cells, we decided to exam-
ine the function of IL-22 during extracellular
bacterial infection of the mucosal system (121).
Citrobacter rodentium, a gram-negative bac-
terium, attaches to murine colon epithelial cells
and induces acute infectious colitis, mimicking
attaching and effacing bacterial infections in the
human. Upon C. rodentium infection, IL-23 and
IL-22 are quickly upregulated in the colon. IL-
23 induces IL-22 production from innate im-
mune cell types including LTi cells, NKp46+
NK-like cells, and DCs (74, 77, 121, 154). IL-
22 is indispensable for host defense during the
early phase of C. rodentium infection (121). IL-
22-deficient mice display much more severe
epithelial damage as well as systemic bacterial
dissemination. Many IL-22−/− mice succumb
within the second week after infection. IL-22
is required for the induction of the Reg family
of antimicrobial peptides from colon epithelial
cells. Reg family proteins are secreted C-type
lectins that may have essential functions in the
prevention of systemic bacterial dissemination.
IL-22 is also required for host defense
against Klebsiella pneumoniae infection in the
lung (124). Blocking IL-22 results in early
death of the infected animals. IL-22 synergizes
with IL-17 in this model to induce lung repair,
proinflammatory chemokines and cytokines,
and Lipocalin-2, which is required for lung
epithelial cells to kill K. pneumoniae. Salmonella
enterica is another gram-negative bacterium
that can cause systemic infection or gastroen-
teritis in humans. Th1 cells and IFN-γ are
essential for the clearance of Salmonella in-
fections. However, during intestinal infection
with Salmonella, IL-23 induces the production
of IL-22 and IL-17 (125, 226). In wild-type
mice, IL-22 is not required for the clearance
of Salmonella infection. In IL-12p35−/− mice,
the development of a Th1 response is com-
promised during the infection. Anti-IL-22
treatment of infected p35−/− mice leads to
liver necrosis, a finding that supports a role for
IL-22 in hepatocyte protection in this model
86 Ouyang et al.
(226). Increased IL-22 and Th17 responses also
have been associated with Mycobacterium tuber-
culosis, Leishmania donovani, and Shigella flexneri
infections (227–230). The roles of IL-22 in
these infections are less clear currently. Data
have shown that IL-22 inhibits M. tuberculosis
in human macrophages (229). However, in a
murine aerosol M. tuberculosis model, IL-22 is
not required for host defense (231).
Contrary to its protective function during
bacterial infections, IL-22 can cause damage in
the intestine during parasite Toxoplasma gondii
infection (232). IL-22 is dispensable for acute
or chronic systemic infections (231). When the
ileum is infected perorally, T. gondii causes
massive necrosis, leading to death in C57BL/6
mice. IL-22−/− mice are resistant to the im-
munopathology induced by T. gondii. Blocking
IL-22 slows the death rate and alleviates the
ileum damage and inflammation after the infec-
tion (232). The downstream mediators of IL-22
in this model are unclear. The potential patho-
logical role of IL-22 during infection has also
been demonstrated in an acute polymicrobial
sepsis model in which blocking IL-22 function
in vivo by IL-22BP attenuates bacterial load and
organ failure (233).
IL-22 in Yeast Infection
T cells are essential for host defense against
yeast infection. Patients without T cells develop
severe systemic candidiasis. Depleting CD4+
T cells in mice significantly increases tissue
damage caused by Candida albicans infection
(234). IL-10 negatively regulates host defense
during C. albicans infection, probably due to its
anti-inflammatory functions. IL-10 deficiency
alleviates systemic C. albicans infection (235).
Recently, IL-17 and Th17 cells have been sug-
gested as cells that play a critical role in host de-
fense against C. albicans infection (70). In vitro,
heat-killed C. albicans hyphae promote human
Th17 differentiation and IL-23 production
(236). In murine models, the IL-17 pathway is
critical for host defense against C. albicans infec-
tion (237). IL-22 is also induced from memory
T cells by C. albicans stimulation (238).
 IY29CH04-Ouyang ARI 4 February 2011 15:27
Interestingly, PBMCs from patients with
chronic mucocutaneous candidiasis (CMC)
produce reduced amounts of IL-17 and IL-22
when stimulated with C. albicans (239). Fur-
thermore, patients with autoimmune polyen-
docrine syndrome type I (APS-I)/autoimmune
polyendocrinopathy candidiasis ectodermal
dystrophy (APECED) also display CMC. Re-
cently, autoantibodies against IL-17A, IL-17F,
and IL-22 have been detected in these patients
(240, 241). These autoantibodies neutralize
the activities of these cytokines, rendering
the patients increasingly susceptible to yeast
infection. In a murine model of oropharyngeal
Annu. Rev. Immunol. 2011.29:71-109. Downloaded from www.annualreviews.org
candidiasis, the IL-17 pathway but not the
IL-22 pathway exerts a host defensive function
(242). However, when mice are infected with
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C. albicans intragastrically, IL-23 induces IL-22
in the stomach (185). Mice deficient for IL-22
have increased dissemination of the yeast into
the stomach and kidney. IL-22 is required for
the upregulation of antimicrobial proteins such
as S100A8, S100A9, RegIIIβ, and RegIIIγ
during the infection (185). Thus, IL-22, as
well as other Th17 cytokines such as IL-17A,
is indispensable for host defense against yeast
infection
Type III IFN in Viral Infections
IL-28A, IL-28B, and IL-29 induce related weak
antiviral responses. The expression of their re-
ceptor, IL-28R, is more restricted than the
widely distributed IFN-α receptor (5). Recent
data suggest, however, that the type III IFN
pathway may be crucial for control of certain
viral infections. Type III IFNs may also offer
better clinical benefit when used for the treat-
ment of viral infections, such as hepatitis C in-
fection, because their receptors are expressed
more specifically on cells that are not from
hematopoietic lineages, which could reduce se-
vere systemic toxicities such as those caused by
type I IFN (243).
IL-28RA is not required for defense against
a panel of viral infections, such as herpes sim-
plex virus type 2 (HSV-2), LCMV, vesicular
stomatitis virus (VSV), and EMCV infections
(244). IL-28RA is required, however, for the
enhanced antiviral activity induced by TLR3
and TLR9 agonists (244). In addition, mice
lacking IL-28RA and IFN-αR are much more
susceptible to highly attenuated influenza A
viruses that are usually nonpathogenic, suggest-
ing that type I and type III IFNs cooperate in
host defense against influenza infections (245).
Indeed, in vitro, the combination of IL-29 with
IFN-α or IFN-γ results in increased inhibi-
tion of viral replication (225). Recent genetic
association studies further support the impor-
tant cooperative functions between the type III
IFN pathway and the type I IFN pathway. A
genetic polymorphism linked to the gene for
IL-28B has been associated with clinical re-
sponse to IFN-α and ribavirin therapy in pa-
tients with chronic hepatitis C infection (246–
249). The nonresponsive allele is reported to
correlate with lower IL-28A/B expression (248,
249). Taken together, IL-28 and IL-29 are es-
sential in regulating host defense against viral
infections. Based on these data, pegylated-rIL-
29 is currently being tested in the clinic for
the treatment of patients with chronic hepati-
tis C infections (243). Future combined strate-
gies with type I and type III IFNs may provide
promising therapies for patients with hepatitis
C infection.
IL-10 FAMILY CYTOKINES
IN THE DEVELOPMENT
OF AUTOIMMUNE AND
INFLAMMATORY DISEASES
IL-10 is associated with many autoimmune dis-
eases because of its anti-inflammatory functions
(250). In the past several years, accumulated
data have also established an important role for
other IL-10 family cytokines in autoimmune
and inflammatory diseases, especially in psori-
asis, IBD, and liver inflammation.
Protective Functions of IL-10 and
IL-22 in the Development of IBD
IBD is a chronic inflammatory disorder of the
gastrointestinal track that manifests either as
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ulcerative colitis (UC) or Crohn’s disease (CD)
(251). The exact causes of IBD are still unclear,
but people believe genetic predisposition and
environmental factors contribute to disease
onset and development. Within the gastroin-
testinal tract, the mucosal epithelial layer
constantly interacts with trillions of microor-
ganisms (252, 253). The resident bacterial
population and the host have evolved a mutu-
ally beneficial symbiosis. To properly maintain
the harmony of the symbiotic environment, the
host defense system composed of both the im-
mune system and the epithelial layer needs to
surmount two challenges (252, 253). First, dur-
ing homeostasis the epithelial cells need to be
competent in sequestering luminal commensal
microbes from penetration into the epithelial
layer. In parallel, the immune system needs to
be maintained in a relatively inert state toward
these resident microorganisms and avoid tissue
damage caused by excessive inflammation.
Second, the immune system and epithelial
system should be able to effectively sense and
control the invasion of various opportunistic
pathogens in the gastrointestinal tract. Im-
portantly, both systems can quickly restore
homeostasis upon clearance of the pathogenic
microbes. Substantial evidence from human
genetic studies and from preclinical IBD
models suggests that failures by either the
mucosal epithelial layer or the immune system
to properly interact with the lumen microbial
community may underlie the pathogenic
processes during IBD.
IL-10 family cytokines have critical func-
tions in regulating the homeostatic states of
the immune system and the mucosal epithelia,
as well as boosting host defense during the
invasion of various microorganisms (254, 255)
(Figure 5). IL-20 subfamily cytokines and
type III IFNs preferentially augment antibac-
terial and antiviral responses from epithelial
cells, respectively. IL-10, on the other hand,
targets various leukocytes, attenuates excessive
immune responses, and protects against the ep-
ithelial damage caused by inflammation. IL-20
family cytokines, especially IL-22, induce the
production of various antimicrobial peptides.
88 Ouyang et al.
IL-22 stimulates the production of chemokines
that attract neutrophils and other phagocytes
to control evading pathogens. These cytokines
can also help to maintain the integrity of ep-
ithelial cells. A major cause of tissue damage is
epithelial cell apoptosis triggered by inflamma-
tion and infection. IL-22 can induce the expres-
sion of antiapoptotic genes and also promotes
proliferation and wound-healing responses,
which help to replenish the damaged tissues.
The association between IL-10 and IBD was
first recognized during the analysis of Il10−/−
mice (256). Although Il10−/− mice develop
normally and have apparent normal antibody
responses, these mice spontaneously develop
colitis that is characterized by abnormal
architecture in the mucosa associated with the
infiltration of various leukocyte subsets. Similar
colitis also develops in Il10rb−/− mice (13). The
enteric microfloras in the gut are necessary for
colitis development in these mice (257). Il10−/−
mice raised in a germ-free environment do
not develop colitis. In addition, administration
of antibiotics before the onset of disease in
these mice prevents colitis (258). Antibiotics
can also attenuate the severity of colitis when
used after the disease has developed. CD4+ T
cells, but not B cells, are essential for the de-
velopment of colitis in Il10−/− mice (259). The
initial proposal that Th1 cells play important
pathogenic roles in this model was due to two
key observations. First, IFN-γ-producing Th1
cells are significantly increased in the gut of
Il10−/− mice during the development of colitis.
Second, IL-10 directly inhibits macrophages
and DCs from producing IL-12, a key driving
factor for Th1 differentiation. IL-12 is a
heterodimeric cytokine consisting of p40 and
p35 subunits, both of which are inhibited by
IL-10 at the transcriptional level in myeloid
cells (260). Later studies have discovered that
the p40 subunit is shared by a novel cytokine,
IL-23 (261). Thus, IL-23 is also inhibited by
IL-10 during inflammation, which prompted
the reanalysis of the role of IL-12 and IL-23 in
colitis development in Il10−/− mice. A detailed
comparison of mice deficient for the p35
subunit of IL-12 or the p19 subunit of IL-23
 IY29CH04-Ouyang ARI 4 February 2011 15:27

Antimicrobial
peptides:
Luminal Reg, S100,
bacteria defensin, etc.

Mucin

Intra- Paneth Goblet

epithelial cell cell
lymphocyte
Neutrophil IL-19, IL-20, and IL-24
DC
Annu. Rev. Immunol. 2011.29:71-109. Downloaded from www.annualreviews.org

Chemokines:
IL-8, etc. IL-22
MΦ IL-26
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IL-12, IL-23, IL-1β,

IL-18, and IL-6

IL-10
Th1, LTi NK γδ
Th17 T cell

Figure 5
IL-10 family cytokines in inflammatory bowel disease. During inflammation, microorganisms in the gastrointestinal tract can induce
the expression of many proinflammatory cytokines, such as IL-23 and IL-1β, from myeloid cells. These cytokines promote the
production of IL-22 from various cell types, including Th17 cells and LTi/NK-like innate cells. On the one hand, IL-22 protects the
epithelial layer from further damage caused by microbes or inflammation. On the other hand, IL-10 from leukocytes directly represses
proinflammatory responses.

led to the conclusion that IL-23, but not IL-12,
mediates the crucial pathogenic functions in
colitis development of Il10−/− mice (262).
IL-17 and IL-6 are downstream of IL-23
and are involved in the pathogenesis, which
supports the idea that Th17 cells but not Th1
cells are required. In vitro, IL-10 can inhibit
IL-23 production from DCs and macrophages.
Therefore, IL-10 is an essential negative
regulator, especially for controlling IL-23
induction, during mucosal inflammation.
The importance of IL-10 in IBD is further
corroborated by its identification as a suscepti-
bility gene for UC in genome-wide association
studies (263). Multiple causal variants may
contribute to the association signal at the IL-10
locus. Elevated IL-10 has also been detected
in the serum of some human UC patients
(264). Interestingly, a high IL-10 serum level is
maintained during the early phase of remission,
whereas C-reactive protein and IL-6 serum
levels return to normal during remission after
an increase during the acute phase. Given
the negative regulatory function of IL-10
in inflammation, people have long proposed
treating human IBD with IL-10. Indeed,
administration of IL-10 has demonstrated
efficacy in various preclinical models of IBD
(265, 266). In humans, however, recombinant
IL-10 has not provided impressive efficacy
in CD (see review in 254). Multiple factors
may contribute to the failure of rIL-10 in
clinical trials. First, systemic administration
may not be sufficient to deliver IL-10 to
the mucosal inflammatory sites where it can
exert its anti-inflammatory functions. Several

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strategies are currently being considered to
efficiently deliver IL-10 to the mucosal sites,
including virus-mediated expression or com-
mensal bacteria–mediated gene delivery. Sec-
ond, in addition to its anti-inflammatory func-
tions, IL-10 also stimulates proinflammatory
responses, such as IFN-γ production, when it
is administered to humans (267). It is unclear
whether this function of IL-10 contributes to
its lack of efficacy in the treatment of IBD.
No genetic association between IL-22 and
IBD has been identified. Elevated IL-22 has
been reported in patients with IBD (60, 268).
Increased Il22 and Il22ra1 messages have been
detected in UC mucosa tissues (269). Serum
samples from CD patients show higher IL-22
but not IFN-γ or IL-17A (270). CD161+ Th17
cells isolated from PBMCs of CD patients
readily produce increased IL-22 and IL-17
when compared with those cells from healthy
controls (271). In addition, the IL-22 levels cor-
relate with disease severity (272). As discussed
above, IL-23 regulates IL-22 production.
Il23R is a CD susceptibility gene. Interestingly,
there is also a remarkable correlation between
serum IL-22 levels and IL-23R minor alleles
and a trend toward lower IL-22 levels in CD
patients having the protective SNPs of Il23
(272). These results are corroborated by the
recent finding that T cells from people bearing
the protective SNP (R381Q) in IL-23R are
hyporesponsive to IL-23 stimulation owing to
the lower expression of IL-23R (S. Pidasheva
and H. Clark, manuscript submitted). These T
cells produce much reduced IL-22 in response
to IL-23 stimulation.
IL-22 is also induced in several preclinical
colitis models such as DSS-induced colitis and
the T cell transfer model of colitis. Similar to
IL-10, IL-22 exerts protective functions in pre-
clinical colitis models. Overexpression of IL-22
in TCRα-deficient mice reduces colonic thick-
ness and disease score (273). In DSS-induced
colitis, blocking the IL-22 pathway leads to
delayed recovery as judged by body weight loss
and histological score (186, 187, 273, 274).
Consistently, transferring T cells from Il22−/−
mice into Rag1−/− Il22−/− mice causes more
90 Ouyang et al.
severe weight loss and mortality than if the
same recipient mice only received wild-type T
cells. IL-10 mediates its protective functions
in colitis models through the reduction of
inflammatory responses of various leukocytes.
IL-22, in contrast, promotes its protective roles
through enhanced tissue innate immunity and
integrity (Figure 5). First, IL-22 can induce
proinflammatory cytokines and chemokines
from colonic epithelial cells and subepithelial
myofibroblasts, such as IL-6 and IL-8 (60,
268). These cytokines and chemokines help
to recruit and activate various leukocytes
in controlling the invading pathogens, thus
preventing further epithelial damage. Second,
IL-22 facilitates goblet cell restitution and
boosts the production of mucus-associated
proteins from goblet cells. The heavily glyco-
sylated mucin family of proteins can form a
static external barrier that sequesters various
luminal microorganisms from direct interac-
tion with epithelial cells (273). Third, IL-22
induces the production and secretion of various
antimicrobial peptides—including defensins,
cathelicidins, and C-type lectins—from intesti-
nal epithelial cells and Paneth cells (121, 186,
187, 273, 274). These antimicrobial peptides
can target the integrity of the bacterial cell wall
and kill or sequester the invading microbes
in the mucin layer. Finally, IL-22 activates
STAT3 in epithelial cells and enhances mu-
cosal wound healing (60, 186, 273, 274). IL-22
induces the production of various proteases
that are important for tissue remodeling. In
addition, IL-22 stimulates the proliferation
and reconstitution of mucosal epithelial cells.
The roles of other IL-10 family cytokines
in IBD are less clear. IL-26 induces STAT1,
STAT3, ERK, and JNK activation in colon
cell lines (275). It also stimulates IL-8 produc-
tion from these cells. In contrast to IL-22, IL-
26 has an antiproliferative effect on intestinal
epithelial cell lines. In addition, elevated IL-
26 has been detected in the inflamed colonic
mucosa of UC and CD patients. The expres-
sion of IL-19, IL-20, and IL-24 in IBD is un-
clear. A recent study with Il19−/− mice indicates
that IL-19, similar to IL-22, may also have a
 IY29CH04-Ouyang ARI 4 February 2011 15:27
protective function in mucosal inflammation
(276). In IL-19-deficient mice, DSS treatment
induces more severe colitis with increased pro-
duction of proinflammatory cytokines such as
IL-12 and TNF-α. IL-28A, IL-28B, and IL-29
have not been examined in IBD, although IL-
28R is expressed in intestinal epithelial cells.
Murine CMV infection increases colonic IL-
28A expression in vivo. IL-28A and IL-29 in-
duce antiviral responses and the production of
IL-8 from intestinal epithelial cell lines (277).
These cytokines also inhibit proliferation of
colon epithelial cell lines. Further studies are
required to elucidate their functions in IBD.
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Role of IL-10 Family Cytokines
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in Liver Protection
Similar to their functions in IBD, IL-10 and
IL-22 exert protective functions during liver in-
flammation. The target cells and mechanisms
used by IL-10 and IL-22 are different. IL-10
targets leukocytes and elicits anti-inflammatory
responses through direct inhibition of the pro-
duction of proinflammatory cytokines, such as
IFN-γ, IL-12, and TNF-α. In contrast, IL-22
stimulates the proliferation of hepatocytes and
the regeneration of the liver. IL-22 also induces
the expression of antiapoptotic genes in hepa-
tocytes and protects them from inflammation-
induced cell death.
IL-10 is induced in the liver and in the serum
quickly after ConA treatment in vivo (278).
Anti-IL-10 antibody treatment before admin-
istration of ConA leads to the development of
a more severe hepatitis as well as increased ex-
pression of IL-12, TNF-α, and IFN-γ produc-
tion in the serum (278). Similar results have also
been observed in IL-10-deficient mice (279).
Conversely, recombinant IL-10 represses these
proinflammatory cytokines and protects the
liver from ConA-induced injury (278, 279).
Furthermore, IL-10 also plays a protective role
in liver injury induced by galactosamine and
lipopolysaccharide (Gal/LPS) (278).
The liver has a high expression of IL-22R
(24). IL-22R and IL-10R2 chains are both ex-
pressed on hepatocytes (280). IL-22 promotes
the proliferation of and has antiapoptotic
effects in hepatocytes (280). IL-22 is upregu-
lated during ConA-induced hepatitis. Exacer-
bated hepatitis after ConA administration, as
measured by increased AST and ALT levels
and severe liver inflammation, occurs when
IL-22 signaling is blocked with a neutralizing
antibody (280) or in Il22−/− mice (61). Th17
cells and NKT cells both produce IL-22 in this
model (61, 281). Interestingly, lack of IL-22 in
a Fas agonist ( Jo-2 mAb)–induced liver injury
and apoptosis model does not alter the severity
of the liver damage (61), implying redundant
pathways for liver protection. Overexpression
of IL-22, however, can further protect the liver
from injury caused by Jo-2 antibody (282).
IL-22 is also involved in liver regeneration.
After a partial hepatectomy in mice, IL-22R is
augmented on hepatocytes (283), which is as-
sociated with an elevated IL-22 protein con-
centration in the serum. Blocking IL-22 by an
antibody reduces proliferation of hepatocytes.
IL-22 can also repress genes involved in lipoge-
nesis, such as Mlxipl, Ppara, Pparg, and Hmgcr,
in the liver (284). Long-term administration of
IL-22 in vivo reduces the levels of triglycerides
and cholesterol in the liver of C57BL/6 and
ob/ob mice fed a high-fat diet (HFD). IL-22
also slightly alleviates hepatic steatosis in HFD-
fed mice.
In conclusion, IL-10 and IL-22 both pro-
tect the liver during inflammation, although
through different mechanisms. IL-20R2 is also
upregulated in the liver upon LPS stimulation
(285), suggesting that IL-19, IL-20, and IL-24
may also exert similar protective functions in
the liver. Future detailed studies on these three
cytokines in liver inflammation will help unveil
their functions.
Role of IL-20 Subfamily Cytokines
in Psoriasis
Although IL-20 subfamily cytokines are impor-
tant for tissue protection, as discussed above,
uncontrolled responses from these cytokines
can be harmful to tissues as well. Psoriasis
is a chronic inflammatory disease of the
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skin characterized by abnormal keratinocyte
differentiation and proliferation, leukocyte
infiltration of the dermis and epidermis, and
increased dilation and growth of blood vessels
(286). The crosstalk between keratinocytes and
leukocytes is essential during the pathogenesis
of psoriasis. Various leukocytes, including T
cells, neutrophils, DCs, and macrophages,
infiltrate the skin and contribute to the inflam-
matory phenotypes of the disease. Immune
cells produce various soluble mediators such as
cytokines and chemokines that orchestrate the
disease manifestations. Over the past several
years, the IL-20 subfamily cytokines have
been identified as the key cytokines involved
in psoriasis. First, IL-20 subfamily cytokines
are elevated in psoriatic skin. Second, IL-20
subfamily cytokines induce many important
pathological features in keratinocytes. Third,
IL-22 and other family members are essential
for the development of psoriasis in preclinical
models. Finally, IL-22 is a downstream cy-
tokine induced by the IL-23 pathway, which is
genetically associated with human psoriasis.
Expression of IL-19, IL-20, IL-22, and IL-
24 cytokines has been detected in psoriatic skin
and not in healthy skin (195, 287, 288). As dis-
cussed above, various leukocytes can produce
IL-20 subfamily cytokines. Myeloid cells and
keratinocytes are potential sources of IL-19,
IL-20, and IL-24 (3, 183, 289). The main source
of IL-22 in skin lesions appears to be T cells. In
psoriatic patients, T cells isolated from the skin
lesions produce much higher levels of IL-22
than do T cells in circulation (290). In addition,
T cell clones generated from psoriatic tissue are
largely CCR6+ IL-22+ (291), presumably Th17
cells or T helper cells that solely produce IL-22,
the so-called Th22 cells (292).
The receptors for IL-20 subfamily cy-
tokines are highly expressed on keratinocytes
(3). IL-19, IL-20, IL-22, and IL-24, but not
IL-26, activate STAT3 either in primary
keratinocytes (3, 195, 199) or in keratinocyte
cell lines (293). All IL-20 subfamily members,
except IL-26, induce the expression of various
antimicrobial peptides including S100 family
genes and β-defensin family genes (3, 114,
92 Ouyang et al.
199, 208). Expression of S100A7 (also called
psoriasin) is a hallmark feature of psoriatic skin.
Furthermore, the IL-20 subfamily cytokines,
especially IL-22, regulate proteins involved
in tissue remodeling, such as MMP1, MMP3,
Kallikreins, marapsin, and platelet-derived
growth factor (3, 188, 199, 294). IL-20
subfamily cytokines also activate proinflam-
matory responses through the induction of
chemokines and cytokines from keratinocytes
(3, 199). Various chemokines, including
CXCL1, CXCL5, and CXCL7, can be induced
by IL-20 subfamily cytokines (3, 199).
IL-22 is the most potent cytokine in the in-
duction of downstream effects described (3). In
fact, IL-22 can induce IL-20 and IL-24, but not
IL-19, expression in keratinocytes (3, 183, 289).
IL-22 can be produced by Th17 cells, which
also secrete IL-17. Interestingly, IL-17 induces
many of the same genes as IL-22, and combin-
ing IL-22 and IL-17 leads to a synergistic induc-
tion of genes, including β-defensins, lipocalin,
and S100 genes (114, 289). An even greater syn-
ergistic effect is seen when keratinocytes are
cultured with IL-22, IL-17, oncostatin M, IL-
1α, and TNF-α (295), suggesting that in addi-
tion to IL-20 subfamily cytokines, other proin-
flammatory cytokines together orchestrate the
pathogenesis of psoriasis. A recent study com-
pared gene expression transcriptome data from
psoriasis and primary keratinocytes treated with
various cytokines (296). Interestingly, there is
very little overlap between gene changes in pso-
riasis samples and cultured keratinocytes that
are treated with any single cytokine. However,
we have noticed that monolayer keratinocytes
do not respond to IL-20 subfamily cytokines
as well as do stratified keratinocytes in recon-
stituted human epidermis (RHE) culture (3).
There is much greater overlap in terms of genes
regulated by IL-20 subfamily cytokines from
RHE and genes regulated in psoriatic skin, sup-
porting an important pathogenic role of this
family of cytokines in psoriasis.
Studies with transgenic mice overexpressing
IL-20 family cytokines further strengthen their
pathogenic roles in psoriasis. Mice overexpress-
ing IL-20, IL-22, and IL-24 under the control
 IY29CH04-Ouyang ARI 4 February 2011 15:27
of various promoters have been generated (17,
297, 298). The phenotypes of these mice are
largely the same, with only a few minor differ-
ences reported. All mice die as neonates smaller
in size than littermates, with IL-22 and IL-24
transgenic mice reported to die within a few
days and IL-24 transgenic mice within a few
hours. The reason for the mortality is not en-
tirely clear. These transgenic mice all exhibit
tight, wrinkled, shiny skin with a thickened epi-
dermis. Histological analysis of the skin reveals
many hallmarks of psoriasis, including epider-
mal hyperplasia (acanthosis) and compact stra-
tum corneum.
Annu. Rev. Immunol. 2011.29:71-109. Downloaded from www.annualreviews.org
Genetic association studies and preclinical
data in psoriatic models also support the func-
tions of IL-20 subfamily cytokines in psoriasis.
by University of Guelph on 05/31/12. For personal use only.
Candidate SNP approaches suggest that IL-19,
IL-20, and IL-24 are associated with suscepti-
bility to psoriasis (299–301). These data have
not been independently confirmed in large-
scale genome-wide association studies. IL-23
plays an important role in the development
of psoriasis. The IL-23 p40 subunit and the
IL-23 receptor have been linked to psoriasis
in genome-wide association studies (302). IL-
23 does not directly target keratinocytes. Its
pathogenic functions on keratinocytes are me-
diated through the IL-20 subfamily cytokines,
especially IL-22. Direct injection of IL-23 in-
duces ear thickening, acanthosis, and dermal
infiltrates, similar to some features in psori-
atic skin (116, 303, 304). The injection of
IL-23 into the back skin of the mouse in-
duces IL-19 and IL-24 expression in the skin.
Consistently, IL-23-induced skin inflammation
and epidermal hyperplasia are attenuated in
Il20rb−/− mice (304). We show that IL-23
injection into the mouse ear induces IL-22,
but not IL-19, IL-20, or IL-24, expression
(116). Ear thickening induced by IL-23 is re-
duced in IL-22 knockout mice or in wild-type
mice when IL-22 is blocked with a neutral-
izing antibody, suggesting that IL-22 medi-
ates the pathogenic effects of IL-23 on ker-
atinocytes. In addition, injection of IL-22 into
the skin of normal mice induces S100 and β-
defensin, plus keratinocyte hyperplasia (305).
In another psoriasis-like mouse model induced
by the transfer of CD4+ CD45RBhi CD25− cells
into SCID mice, neutralization of either IL-22
or IL-23 prevents disease development as well
(305). Finally, a human xenograft model has re-
cently been described in which human psoriatic
skin can be transplanted onto immunodeficient
mice. In this model, treating transplanted mice
with blocking antibodies to IL-20 resolved the
psoriasis condition (306).
In summary, IL-20 subfamily cytokines are
essential in mediating some of the key patho-
logical features during the course of psoriasis.
Blockade of p40, the common subunit of IL-12
and IL-23, has shown great efficacy in psoria-
sis (307). Given the importance of IL-23 in the
induction of IL-22 and that blockade of IL-22
in mice ameliorates IL-23-induced skin inflam-
mation, blocking IL-22 and other family cy-
tokines could be a novel therapeutic approach
in the treatment of psoriasis.
Association of IL-10 Family Cytokines
with Other Autoimmune and
Inflammatory Diseases
IL-10, IL-19, IL-20, IL-22, and IL-24 are
upregulated in the synovial fluid mononuclear
cells of rheumatoid arthritis (RA) (308, 309).
Immunohistological analysis suggests that
IL-19 and IL-22 are expressed by synovial
fibroblasts and macrophages (310, 311). IL-20
is observed in sublining mononuclear cells,
whereas IL-24 is detected in mononuclear cells
and endothelial cells (309). Furthermore, in
the PBMCs and joints of RA patients, there are
increased numbers of Th17 cells, which may
contribute to the production of IL-22 as well
(291, 312). IL-20R1, IL-20R2, and IL-22R
are expressed on lining and sublining layers of
RA synovial tissues (310, 311). IL-19 increases
the production of IL-6 by RA synovium and
reduces apoptosis of the synovial cells (310).
IL-20 promotes synovial cells to secrete CCL2,
IL-6, and IL-8, as well as endothelial cell pro-
liferation (313). Similarly, IL-22 induces pro-
liferation of synovial fibroblasts and production
of CCL2 by these cells (311). Soluble IL-20R1,
which could block IL-19, IL-20, and IL-24,
www.annualreviews.org • IL-10 Family Cytokines in Immunity 93
 IY29CH04-Ouyang
Annu. Rev. Immunol. 2011.29:71-109. Downloaded from www.annualreviews.org
by University of Guelph on 05/31/12. For personal use only.
ARI 4 February 2011 15:27
attenuates disease severity in rats with collagen-
induced arthritis (CIA) (313). Elevated IL-22
is reported in a mouse model of CIA. Il22−/−
mice have a delayed onset of disease, reduced
disease severity, and decreased proinflamma-
tory cytokine expression in the joints compared
with those in wild-type mice with CIA (314).
IL-20 and IL-22 are reportedly associated
with lupus (315, 316). IL-20 targets renal
mesangial cells, suggesting its potential role in
lupus nephritis (315). IL-22 levels in plasma,
however, are negatively correlated with disease
activity in patients with systemic lupus erythe-
matosus (316). The functions of these cytokines
in lupus require further detailed study. Inter-
estingly, serum IL-10 levels are elevated in lu-
pus. Given the role of IL-10 in enhancing B cell
proliferation and differentiation, antagonists of
IL-10 have been considered for the treatment
of lupus.
IL-22 induces disruption of the blood-brain
barrier (317). In preclinical EAE, a model for
human multiple sclerosis, however, IL-22 is
not required for the development of the dis-
ease (123). As discussed above, IL-22 protects
the lung from K. pneumonia infection (200). Its
role in lung inflammation has not been fully
addressed. One study in a preclinical asthma
model found that IL-22 inhibits eosinophil re-
cruitment to the lung, suggesting a negative
role for IL-22 in asthma (318). Patients with sta-
ble chronic obstructive pulmonary disease have
elevated concentrations of IL-22+ Th17 cells in
the lungs (319). Furthermore, IL-19 is upregu-
lated in asthma patients (201). IL-4, IL-13, IL-
17A, and IL-22 can all induce the production
of IL-19 from human bronchial epithelial cells
(184). The role of IL-19 in asthma development
is currently unclear.
In addition to its role in liver protection,
IL-22 can also reduce damage to the heart
during inflammatory responses. Exogenous
IL-22 attenuates the damage from experimental
DISCLOSURE STATEMENT
W. Ouyang, S. Rutz, N.K. Crellin, and S.G. Hymowitz are employees of Genentech, Inc. The
authors are not aware of any affiliations, memberships, funding, or financial holdings that might
be perceived as affecting the objectivity of this review.
94 Ouyang et al.
autoimmune myocarditis in rats (320). In ad-
dition, IL-22 deficiency results in accelerated
heart rejection in an allograft transplantation
model (321). The functions of other IL-10 fam-
ily cytokines, except IL-10 and IL-22, in or-
gan protection are largely unexplored. A recent
genome-wide association study has linked the
IL-10 locus, including IL-10, IL-19, and IL-20,
with type I diabetes (322). No functional data of
these cytokines have been reported in diabetes.
Significant future research will be required to
fully elucidate the role of IL-10 family members
in autoimmune and inflammatory diseases.
CONCLUSION
IL-10 family cytokines have very diverse cel-
lular targets and functions. They have a deep
evolutionary connection to the IFN family;
however, their functional roles are much
broader. The central functions of IL-10 family
cytokines converge on protection of organs and
tissues from damage caused by infections and
by inflammatory responses. Three key types
of responses are triggered by this family of cy-
tokines. First, type III IFNs, IL-28A, IL-28B,
and IL-29, stimulate innate antiviral responses
from epithelial cells and protect organ and
tissue from damage caused by viral infections.
Second, the IL-20 subfamily cytokines, IL-
19, IL-20, IL-22, IL-24, and IL-26, act on
tissue epithelial cells during extracellular
bacterial and yeast infections to boost innate
antimicrobial responses. In addition, IL-20
subfamily cytokines induce wound-healing
responses and promote the integrity of various
tissues and organs. Finally, IL-10 inhibits
the innate and adaptive immune responses
from leukocytes and limits the potential tissue
damage caused by inflammation. IL-10 family
cytokines, therefore, are essential for host
defense against various infections and the
development of many autoimmune diseases.
 IY29CH04-Ouyang ARI 4 February 2011 15:27

LITERATURE CITED
1. Pestka S, Krause CD, Sarkar D, Walter MR, Shi Y, Fisher PB. 2004. Interleukin-10 and related cytokines
and receptors. Annu. Rev. Immunol. 22:929–79
2. Moore K, de Waal Malefyt R, Coffman R, O’Garra A. 2001. Interleukin-10 and the interleukin-10
receptor. Annu. Rev. Immunol. 19:683–765
3. Sa SM, Valdez PA, Wu J, Jung K, Zhong F, et al. 2007. The effects of IL-20 subfamily cytokines
on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic
adaptive immunity in psoriasis. J. Immunol. 178:2229–40
4. Fox BA, Sheppard PO, O’Hara PJ. 2009. The role of genomic data in the discovery, annotation and
evolutionary interpretation of the interferon-lambda family. PLoS ONE 4:e4933
5. Uze G, Monneron D. 2007. IL-28 and IL-29: newcomers to the interferon family. Biochimie 89:729–34
6. Fiorentino DF, Bond MW, Mosmann TR. 1989. Two types of mouse T helper cell. IV. Th2 clones
secrete a factor that inhibits cytokine production by Th1 clones. J. Exp. Med. 170:2081–95
7. Moore KW, Vieira P, Fiorentino DF, Trounstine ML, Khan TA, Mosmann TR. 1990. Homology of
Annu. Rev. Immunol. 2011.29:71-109. Downloaded from www.annualreviews.org

cytokine synthesis inhibitory factor (IL-10) to the Epstein-Barr virus gene BCRFI. Science 248:1230–34
8. Vieira P, de Waal-Malefyt R, Dang MN, Johnson KE, Kastelein R, et al. 1991. Isolation and expression of
human cytokine synthesis inhibitory factor cDNA clones: homology to Epstein-Barr virus open reading
by University of Guelph on 05/31/12. For personal use only.

frame BCRFI. Proc. Natl. Acad. Sci. USA 88:1172–76

9. Ho AS, Liu Y, Khan TA, Hsu DH, Bazan JF, Moore KW. 1993. A receptor for interleukin 10 is related
to interferon receptors. Proc. Natl. Acad. Sci. USA 90:11267–71
10. Liu Y, Wei SH, Ho AS, de Waal Malefyt R, Moore KW. 1994. Expression cloning and characterization
of a human IL-10 receptor. J. Immunol. 152:1821–29
11. Kotenko SV, Krause CD, Izotova LS, Pollack BP, Wu W, Pestka S. 1997. Identification and functional
characterization of a second chain of the interleukin-10 receptor complex. EMBO J. 16:5894–903
12. Lutfalla G, Gardiner K, Uze G. 1993. A new member of the cytokine receptor gene family maps on
chromosome 21 at less than 35 kb from IFNAR. Genomics 16:366–73
13. Spencer SD, Di Marco F, Hooley J, Pitts-Meek S, Bauer M, et al. 1998. The orphan receptor CRF2-4
is an essential subunit of the interleukin 10 receptor. J. Exp. Med. 187:571–78
14. Jones E, Flavell R. 2005. Distal enhancer elements transcribe intergenic RNA in the IL-10 family gene
cluster. J. Immunol. 175:7437–46
15. Jiang H, Lin JJ, Su ZZ, Goldstein NI, Fisher PB. 1995. Subtraction hybridization identifies a novel
melanoma differentiation associated gene, mda-7, modulated during human melanoma differentiation,
growth and progression. Oncogene 11:2477–86
16. Gallagher G, Dickensheets H, Eskdale J, Izotova LS, Mirochnitchenko OV, et al. 2000. Cloning, expres-
sion and initial characterization of interleukin-19 (IL-19), a novel homologue of human interleukin-10
(IL-10). Genes Immun. 1:442–50
17. Blumberg H, Conklin D, Xu WF, Grossmann A, Brender T, et al. 2001. Interleukin 20: discovery,
receptor identification, and role in epidermal function. Cell 104:9–19
18. Parrish-Novak J, Xu W, Brender T, Yao L, Jones C, et al. 2002. Interleukins 19, 20, and 24 signal
through two distinct receptor complexes. Differences in receptor-ligand interactions mediate unique
biological functions. J. Biol. Chem. 277:47517–23
19. Wang M, Tan Z, Zhang R, Kotenko SV, Liang P. 2002. Interleukin 24 (MDA-7/MOB-5) signals through
two heterodimeric receptors, IL-22R1/IL-20R2 and IL-20R1/IL-20R2. J. Biol. Chem. 277:7341–47
20. Dumoutier L, Leemans C, Lejeune D, Kotenko SV, Renauld JC. 2001. Cutting edge: STAT activation
by IL-19, IL-20 and mda-7 through IL-20 receptor complexes of two types. J. Immunol. 167:3545–49
21. Dumoutier L, Louahed J, Renauld JC. 2000. Cloning and characterization of IL-10-related T cell-
derived inducible factor (IL-TIF), a novel cytokine structurally related to IL-10 and inducible by IL-9.
J. Immunol. 164:1814–19
22. Knappe A, Hor S, Wittmann S, Fickenscher H. 2000. Induction of a novel cellular homolog of
interleukin-10, AK155, by transformation of T lymphocytes with herpesvirus saimiri. J. Virol. 74:3881–
87

www.annualreviews.org • IL-10 Family Cytokines in Immunity 95

 IY29CH04-Ouyang ARI 4 February 2011 15:27

23. Xie MH, Aggarwal S, Ho WH, Foster J, Zhang Z, et al. 2000. Interleukin (IL)-22, a novel human
cytokine that signals through the interferon receptor-related proteins CRF2–4 and IL-22R. J. Biol.
Chem. 275:31335–39
24. Kotenko SV, Izotova LS, Mirochnitchenko OV, Esterova E, Dickensheets H, et al. 2001. Identification
of the functional interleukin-22 (IL-22) receptor complex: the IL-10R2 chain (IL-10Rβ) is a common
chain of both the IL-10 and IL-22 (IL-10-related T cell-derived inducible factor, IL-TIF) receptor
complexes. J. Biol. Chem. 276:2725–32
25. Sheikh F, Baurin VV, Lewis-Antes A, Shah NK, Smirnov SV, et al. 2004. Cutting edge: IL-26 signals
through a novel receptor complex composed of IL-20 receptor 1 and IL-10 receptor 2. J. Immunol.
172:2006–10
26. Kotenko SV, Izotova LS, Mirochnitchenko OV, Esterova E, Dickensheets H, et al. 2001. Identification,
cloning, and characterization of a novel soluble receptor that binds IL-22 and neutralizes its activity.
J. Immunol. 166:7096–103
27. Dumoutier L, Lejeune D, Hor S, Fickenscher H, Renauld JC. 2003. Cloning of a new type II cytokine
receptor activating signal transducer and activator of transcription (STAT)1, STAT2 and STAT3.
Annu. Rev. Immunol. 2011.29:71-109. Downloaded from www.annualreviews.org

Biochem. J. 370:391–96
28. Xu W, Presnell SR, Parrish-Novak J, Kindsvogel W, Jaspers S, et al. 2001. A soluble class II cytokine
receptor, IL-22RA2, is a naturally occurring IL-22 antagonist. Proc. Natl. Acad. Sci. USA 98:9511–16
by University of Guelph on 05/31/12. For personal use only.

29. Dumoutier L, Van Roost E, Ameye G, Michaux L, Renauld JC. 2000. IL-TIF/IL-22: genomic organi-
zation and mapping of the human and mouse genes. Genes Immun. 1:488–94
30. Wang T, Dı́az-Rosales P, Martin SA, Secombes CJ. 2009. Cloning of a novel interleukin (IL)-20-like
gene in rainbow trout Oncorhynchus mykiss gives an insight into the evolution of the IL-10 family. Dev.
Comp. Immunol. 34:158–67
31. Kotenko SV, Gallagher G, Baurin VV, Lewis-Antes A, Shen M, et al. 2003. IFN-λs mediate antiviral
protection through a distinct class II cytokine receptor complex. Nat. Immunol. 4:69–77
32. Sheppard P, Kindsvogel W, Xu W, Henderson K, Schlutsmeyer S, et al. 2003. IL-28, IL-29 and their
class II cytokine receptor IL-28R. Nat. Immunol. 4:63–68
33. Onoguchi K, Yoneyama M, Takemura A, Akira S, Taniguchi T, et al. 2007. Viral infections activate
types I and III interferon genes through a common mechanism. J. Biol. Chem. 282:7576–81
34. Gad HH, Dellgren C, Hamming OJ, Vends S, Paludan SR, Hartmann R. 2009. Interferon-λ is func-
tionally an interferon but structurally related to the interleukin-10 family. J. Biol. Chem. 284:20869–75
35. Sommereyns C, Paul S, Staeheli P, Michiels T. 2008. IFN-lambda (IFN-λ) is expressed in a tissue-
dependent fashion and primarily acts on epithelial cells in vivo. PLoS Pathog. 4:e1000017
36. Witte K, Gruetz G, Volk HD, Looman AC, Asadullah K, et al. 2009. Despite IFN-λ receptor expres-
sion, blood immune cells, but not keratinocytes or melanocytes, have an impaired response to type III
interferons: implications for therapeutic applications of these cytokines. Genes Immun. 10:702–14
37. Krause CD, Mei E, Mirochnitchenko O, Lavnikova N, Xie J, et al. 2006. Interactions among the com-
ponents of the interleukin-10 receptor complex. Biochem. Biophys. Res. Commun. 340:377–85
38. Trivella DB, Ferreira-Junior JR, Dumoutier L, Renauld JC, Polikarpov I. 2010. Structure and function
of interleukin-22 and other members of the interleukin-10 family. Cell. Mol. Life Sci. 67:2909–35
39. Ealick SE, Cook WJ, Vijay-Kumar S, Carson M, Nagabhushan TL, et al. 1991. Three-dimensional
structure of recombinant human interferon-γ. Science 252:698–702
40. Walter MR, Nagabhushan TL. 1995. Crystal structure of interleukin 10 reveals an interferon γ-like
fold. Biochemistry 34:12118–25
41. Zdanov A, Schalk-Hihi C, Gustchina A, Tsang M, Weatherbee J, Wlodawer A. 1995. Crystal structure
of interleukin-10 reveals the functional dimer with an unexpected topological similarity to interferon γ.
Structure 3:591–601
42. Josephson K, DiGiacomo R, Indelicato SR, Iyo AH, Nagabhushan TL, et al. 2000. Design and analysis
of an engineered human interleukin-10 monomer. J. Biol. Chem. 275:13552–57
43. de Oliveira Neto M, Ferreira JR Jr, Colau D, Fischer H, Nascimento AS, et al. 2008. Interleukin-22
forms dimers that are recognized by two interleukin-22R1 receptor chains. Biophys. J. 94:1754–65
44. Nagem RA, Colau D, Dumoutier L, Renauld JC, Ogata C, Polikarpov I. 2002. Crystal structure of
recombinant human interleukin-22. Structure 10:1051–62

96 Ouyang et al.
 IY29CH04-Ouyang ARI 4 February 2011 15:27

45. Jones BC, Logsdon NJ, Walter MR. 2008. Structure of IL-22 bound to its high-affinity IL-22R1 chain.
Structure 16:1333–44
46. Walter MR, Windsor WT, Nagabhushan TL, Lundell DJ, Lunn CA, et al. 1995. Crystal structure of a
complex between interferon-γ and its soluble high-affinity receptor. Nature 376:230–35
47. Josephson K, Logsdon NJ, Walter MR. 2001. Crystal structure of the IL-10/IL-10R1 complex reveals
a shared receptor binding site. Immunity 15:35–46
48. Bleicher L, de Moura PR, Watanabe L, Colau D, Dumoutier L, et al. 2008. Crystal structure of the
IL-22/IL-22R1 complex and its implications for the IL-22 signaling mechanism. FEBS Lett. 582:2985–92
49. de Moura PR, Watanabe L, Bleicher L, Colau D, Dumoutier L, et al. 2009. Crystal structure of a soluble
decoy receptor IL-22BP bound to interleukin-22. FEBS Lett. 583:1072–77
50. de Vos AM, Ultsch M, Kossiakoff AA. 1992. Human growth hormone and extracellular domain of its
receptor: crystal structure of the complex. Science 255:306–12
51. Yoon SI, Logsdon NJ, Sheikh F, Donnelly RP, Walter MR. 2006. Conformational changes mediate
interleukin-10 receptor 2 (IL-10R2) binding to IL-10 and assembly of the signaling complex. J. Biol.
Chem. 281:35088–96
Annu. Rev. Immunol. 2011.29:71-109. Downloaded from www.annualreviews.org

52. Yoon SI, Jones BC, Logsdon NJ, Harris BD, Deshpande A, et al. 2010. Structure and mechanism of
receptor sharing by the IL-10R2 common chain. Structure 18:638–48
53. Wang X, Lupardus P, Laporte SL, Garcia KC. 2009. Structural biology of shared cytokine receptors.
by University of Guelph on 05/31/12. For personal use only.

Annu. Rev. Immunol. 27:29–60

54. Ho AS, Wei SH, Mui AL, Miyajima A, Moore KW. 1995. Functional regions of the mouse interleukin-10
receptor cytoplasmic domain. Mol. Cell. Biol. 15:5043–53
55. Finbloom DS, Winestock KD. 1995. IL-10 induces the tyrosine phosphorylation of tyk2 and Jak1 and
the differential assembly of STAT1 alpha and STAT3 complexes in human T cells and monocytes.
J. Immunol. 155:1079–90
56. Meraz MA, White JM, Sheehan KC, Bach EA, Rodig SJ, et al. 1996. Targeted disruption of the Stat1 gene
in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell 84:431–42
57. Takeda K, Clausen BE, Kaisho T, Tsujimura T, Terada N, et al. 1999. Enhanced Th1 activity and
development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity
10:39–49
58. Lejeune D, Dumoutier L, Constantinescu S, Kruijer W, Schuringa JJ, Renauld JC. 2002. Interleukin-22
(IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line.
Pathways that are shared with and distinct from IL-10. J. Biol. Chem. 277:33676–82
59. Dumoutier L, de Meester C, Tavernier J, Renauld JC. 2009. New activation modus of STAT3: a tyrosine-
less region of the interleukin-22 receptor recruits STAT3 by interacting with its coiled-coil domain.
J. Biol. Chem. 284:26377–84
60. Brand S, Beigel F, Olszak T, Zitzmann K, Eichhorst ST, et al. 2006. IL-22 is increased in active Crohn’s
disease and promotes proinflammatory gene expression and intestinal epithelial cell migration. Am. J.
Physiol. Gastrointest. Liver Physiol. 290:G827–38
61. Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Karow M, Flavell RA. 2007. Interleukin-
22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity
27:647–59
62. Weber GF, Gaertner FC, Erl W, Janssen KP, Blechert B, et al. 2006. IL-22-mediated tumor growth
reduction correlates with inhibition of ERK1/2 and AKT phosphorylation and induction of cell cycle
arrest in the G2-M phase. J. Immunol. 177:8266–72
63. O’Garra A, Vieira P. 2007. T(H)1 cells control themselves by producing interleukin-10. Nat. Rev. Im-
munol. 7:425–28
64. Trinchieri G. 2007. Interleukin-10 production by effector T cells: Th1 cells show self control. J. Exp.
Med. 204:239–43
65. Roncarolo MG, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K, Levings MK. 2006. Interleukin-
10-secreting type 1 regulatory T cells in rodents and humans. Immunol. Rev. 212:28–50
66. Maynard C, Weaver C. 2008. Diversity in the contribution of interleukin-10 to T-cell-mediated immune
regulation. Immunol. Rev. 226:219–33

www.annualreviews.org • IL-10 Family Cytokines in Immunity 97

 IY29CH04-Ouyang ARI 4 February 2011 15:27

67. Maloy K, Powrie F. 2001. Regulatory T cells in the control of immune pathology. Nat. Immunol. 2:816–22
68. Saraiva M, O’Garra A. 2010. The regulation of IL-10 production by immune cells. Nat. Rev. Immunol.
10:170–81
69. Lampropoulou V, Calderon-Gomez E, Roch T, Neves P, Shen P, et al. 2010. Suppressive functions
of activated B cells in autoimmune diseases reveal the dual roles of Toll-like receptors in immunity.
Immunol. Rev. 233:146–61
70. Ouyang W, Kolls JK, Zheng Y. 2008. The biological functions of T helper 17 cell effector cytokines in
inflammation. Immunity 28:454–67
71. Colonna M. 2009. Interleukin-22-producing natural killer cells and lymphoid tissue inducer-like cells in
mucosal immunity. Immunity 31:15–23
72. Martin B, Hirota K, Cua DJ, Stockinger B, Veldhoen M. 2009. Interleukin-17-producing γδ T cells
selectively expand in response to pathogen products and environmental signals. Immunity 31:321–30
73. Sutton CE, Lalor SJ, Sweeney CM, Brereton CF, Lavelle EC, Mills KH. 2009. Interleukin-1 and IL-
23 induce innate IL-17 production from γδ T cells, amplifying Th17 responses and autoimmunity.
Immunity 31:331–41
Annu. Rev. Immunol. 2011.29:71-109. Downloaded from www.annualreviews.org

74. Takatori H, Kanno Y, Watford WT, Tato CM, Weiss G, et al. 2009. Lymphoid tissue inducer-like cells
are an innate source of IL-17 and IL-22. J. Exp. Med. 206:35–41
75. Cupedo T, Crellin NK, Papazian N, Rombouts EJ, Weijer K, et al. 2009. Human fetal lymphoid
by University of Guelph on 05/31/12. For personal use only.

tissue-inducer cells are interleukin 17-producing precursors to RORC+ CD127+ natural killer-like cells.
Nat. Immunol. 10:66–74
76. Wolk K, Kunz S, Asadullah K, Sabat R. 2002. Cutting edge: immune cells as sources and targets of the
IL-10 family members? J. Immunol. 168:5397–402
77. Cella M, Fuchs A, Vermi W, Facchetti F, Otero K, et al. 2009. A human natural killer cell subset provides
an innate source of IL-22 for mucosal immunity. Nature 457:722–25
78. Manel N, Unutmaz D, Littman DR. 2008. The differentiation of human T(H)-17 cells requires trans-
forming growth factor-β and induction of the nuclear receptor RORγt. Nat. Immunol. 9:641–49
79. Wilson NJ, Boniface K, Chan JR, McKenzie BS, Blumenschein WM, et al. 2007. Development, cytokine
profile and function of human interleukin 17-producing helper T cells. Nat. Immunol. 8:950–57
80. Hori S, Nomura T, Sakaguchi S. 2003. Control of regulatory T cell development by the transcription
factor Foxp3. Science 299:1057–61
81. Vieira P, Christensen J, Minaee S, O’Neill E, Barrat F, et al. 2004. IL-10-secreting regulatory T cells
do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+ CD25+
regulatory T cells. J. Immunol. 172:5986–93
82. Maynard CL, Harrington LE, Janowski KM, Oliver JR, Zindl CL, et al. 2007. Regulatory T cells
expressing interleukin 10 develop from Foxp3+ and Foxp3− precursor cells in the absence of interleukin
10. Nat. Immunol. 8:931–41
83. Hawrylowicz CM, O’Garra A. 2005. Potential role of interleukin-10-secreting regulatory T cells in
allergy and asthma. Nat. Rev. Immunol. 5:271–83
84. Belkaid Y. 2007. Regulatory T cells and infection: a dangerous necessity. Nat. Rev. Immunol. 7:875–88
85. Josefowicz SZ, Rudensky A. 2009. Control of regulatory T cell lineage commitment and maintenance.
Immunity 30:616–25
86. Shevach EM. 2009. Mechanisms of Foxp3+ T regulatory cell-mediated suppression. Immunity 30:636–45
87. de la Rosa M, Rutz S, Dorninger H, Scheffold A. 2004. Interleukin-2 is essential for CD4+ CD25+
regulatory T cell function. Eur. J. Immunol. 34:2480–88
88. Barthlott T, Moncrieffe H, Veldhoen M, Atkins CJ, Christensen J, et al. 2005. CD25+ CD4+ T cells
compete with naive CD4+ T cells for IL-2 and exploit it for the induction of IL-10 production. Int.
Immunol. 17:279–88
89. O’Garra A, Vieira P. 2004. Regulatory T cells and mechanisms of immune system control. Nat. Med.
10:801–5
90. Shevach EM. 2006. From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity 25:195–
201
91. Roncarolo M, Bacchetta R, Bordignon C, Narula S, Levings M. 2001. Type 1 T regulatory cells. Immunol.
Rev. 182:68–79

98 Ouyang et al.
 IY29CH04-Ouyang ARI 4 February 2011 15:27

92. Barrat F, Cua D, Boonstra A, Richards D, Crain C, et al. 2002. In vitro generation of interleukin 10-
producing regulatory CD4+ T cells is induced by immunosuppressive drugs and inhibited by T helper
type 1 (Th1)- and Th2-inducing cytokines. J. Exp. Med. 195:603–16
93. Zhu J, Min B, Hu-Li J, Watson C, Grinberg A, et al. 2004. Conditional deletion of Gata3 shows its
essential function in T(H)1-T(H)2 responses. Nat. Immunol. 5:1157–65
94. Shoemaker J, Saraiva M, O’Garra A. 2006. GATA-3 directly remodels the IL-10 locus independently of
IL-4 in CD4+ T cells. J. Immunol. 176:3470–79
95. Chang H, Helbig C, Tykocinski L, Kreher S, Koeck J, et al. 2007. Expression of IL-10 in Th memory
lymphocytes is conditional on IL-12 or IL-4, unless the IL-10 gene is imprinted by GATA-3. Eur. J.
Immunol. 37:807–17
96. Stumhofer J, Silver J, Laurence A, Porrett P, Harris T, et al. 2007. Interleukins 27 and 6 induce STAT3-
mediated T cell production of interleukin 10. Nat. Immunol. 8:1363–71
97. Veldhoen M, Uyttenhove C, van Snick J, Helmby H, Westendorf A, et al. 2008. Transforming growth
factor-β “reprograms” the differentiation of T helper 2 cells and promotes an interleukin 9-producing
subset. Nat. Immunol. 9:1341–46
Annu. Rev. Immunol. 2011.29:71-109. Downloaded from www.annualreviews.org

98. Dardalhon V, Awasthi A, Kwon H, Galileos G, Gao W, et al. 2008. IL-4 inhibits TGF-β-induced
Foxp3+ T cells and, together with TGF-β, generates IL-9+ IL-10+ Foxp3− effector T cells.
Nat. Immunol. 9:1347–55
by University of Guelph on 05/31/12. For personal use only.

99. Wong MT, Ye JJ, Alonso MN, Landrigan A, Cheung RK, et al. 2010. Regulation of human Th9
differentiation by type I interferons and IL-21. Immunol. Cell Biol. 88:624–31
100. Schaefer G, Venkataraman C, Schindler U. 2001. Cutting edge: FISP (IL-4-induced secreted protein),
a novel cytokine-like molecule secreted by Th2 cells. J. Immunol. 166:5859–63
101. Assenmacher M, Schmitz J, Radbruch A. 1994. Flow cytometric determination of cytokines in acti-
vated murine T helper lymphocytes: expression of interleukin-10 in interferon-γ and in interleukin-4-
expressing cells. Eur. J. Immunol. 24:1097–101
102. Del Prete G, De Carli M, Almerigogna F, Giudizi MG, Biagiotti R, Romagnani S. 1992. Human
IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cell clones and inhibits their
antigen-specific proliferation and cytokine production. J. Immunol. 150:353–60
103. Meyaard L, Hovenkamp E, Otto SA, Miedema F. 1996. IL-12-induced IL-10 production by human T
cells as a negative feedback for IL-12-induced immune responses. J. Immunol. 156:2776–82
104. Gerosa F, Paganin C, Peritt D, Paiola F, Scupoli M, et al. 1996. Interleukin-12 primes human CD4 and
CD8 T cell clones for high production of both interferon-γand interleukin-10. J. Exp. Med. 183:2559–69
105. Saraiva M, Christensen J, Veldhoen M, Murphy TL, Murphy KM, O’Garra A. 2009. Interleukin-10
production by Th1 cells requires interleukin-12-induced STAT4 transcription factor and ERK MAP
kinase activation by high antigen dose. Immunity 31:209–19
106. Fitzgerald D, Zhang G, El-Behi M, Fonseca-Kelly Z, Li H, et al. 2007. Suppression of autoimmune
inflammation of the central nervous system by interleukin 10 secreted by interleukin 27-stimulated
T cells. Nat. Immunol. 8:1372–79
107. Batten M, Kljavin NM, Li J, Walter MJ, de Sauvage FJ, Ghilardi N. 2008. Cutting edge: IL-27 is a
potent inducer of IL-10 but not FoxP3 in murine T cells. J. Immunol. 180:2752–56
108. Pot C, Jin H, Awasthi A, Liu SM, Lai C-Y, et al. 2009. Cutting edge: IL-27 induces the transcription
factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to
promote differentiation of IL-10-producing Tr1 cells. J. Immunol. 183:797–801
109. Anderson CF, Stumhofer JS, Hunter CA, Sacks D. 2009. IL-27 regulates IL-10 and IL-17 from CD4+
cells in nonhealing Leishmania major infection. J. Immunol. 183:4619–27
110. Murugaiyan G, Mittal A, Lopez-Diego R, Maier LM, Anderson DE, Weiner HL. 2009. IL-27 is a key
regulator of IL-10 and IL-17 production by human CD4+ T cells. J. Immunol. 183:2435–43
111. Awasthi A, Carrier Y, Peron J, Bettelli E, Kamanaka M, et al. 2007. A dominant function for interleukin
27 in generating interleukin 10-producing anti-inflammatory T cells. Nat. Immunol. 8:1380–89
112. McGeachy M, Bak-Jensen K, Chen Y, Tato C, Blumenschein W, et al. 2007. TGF-β and IL-6 drive the
production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat. Immunol.
8:1390–97

www.annualreviews.org • IL-10 Family Cytokines in Immunity 99

 IY29CH04-Ouyang ARI 4 February 2011 15:27

113. Gurney AL. 2004. IL-22, a Th1 cytokine that targets the pancreas and select other peripheral tissues.
Int. Immunopharmacol. 4:669–77
114. Liang SC, Tan XY, Luxenberg DP, Karim R, Dunussi-Joannopoulos K, et al. 2006. Interleukin (IL)-22
and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides.
J. Exp. Med. 203:2271–79
115. Chung Y, Yang X, Chang SH, Ma L, Tian Q, Dong C. 2006. Expression and regulation of IL-22 in the
IL-17-producing CD4+ T lymphocytes. Cell Res. 16:902–7
116. Zheng Y, Danilenko D, Valdez P, Kasman I, Eastham-Anderson J, et al. 2007. Interleukin-22, a T(H)17
cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 445:648–51
117. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. 2006. TGFβ in the context of an
inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity
24:179–89
118. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, et al. 2006. Reciprocal developmental pathways for
the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–38
119. Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC, et al. 2006. Transforming growth
Annu. Rev. Immunol. 2011.29:71-109. Downloaded from www.annualreviews.org

factor-β induces development of the T(H)17 lineage. Nature 441:231–34

120. Duhen T, Geiger R, Jarrossay D, Lanzavecchia A, Sallusto F. 2009. Production of interleukin 22 but
not interleukin 17 by a subset of human skin-homing memory T cells. Nat. Immunol. 10:857–63
by University of Guelph on 05/31/12. For personal use only.

121. Zheng Y, Valdez PA, Danilenko DM, Hu Y, Sa SM, et al. 2008. Interleukin-22 mediates early host
defense against attaching and effacing bacterial pathogens. Nat. Med. 14:282–89
122. Nurieva R, Yang XO, Martinez G, Zhang Y, Panopoulos AD, et al. 2007. Essential autocrine regulation
by IL-21 in the generation of inflammatory T cells. Nature 448:480–83
123. Kreymborg K, Etzensperger R, Dumoutier L, Haak S, Rebollo A, et al. 2007. IL-22 is expressed by
Th17 cells in an IL-23-dependent fashion, but not required for the development of autoimmune en-
cephalomyelitis. J. Immunol. 179:8098–104
124. Aujla S, Chan Y, Zheng M, Fei M, Askew D, et al. 2008. IL-22 mediates mucosal host defense against
Gram-negative bacterial pneumonia. Nat. Med. 14:275–81
125. Siegemund S, Schütze N, Schulz S, Wolk K, Nasilowska K, et al. 2009. Differential IL-23 requirement
for IL-22 and IL-17A production during innate immunity against Salmonella enterica serovar Enteritidis.
Int. Immunol. 21:555–65
126. Mus AMC, Cornelissen F, Asmawidjaja PS, van Hamburg JP, Boon L, et al. 2010. Interleukin-23 pro-
motes Th17 differentiation by inhibiting T-bet and FoxP3 and is required for elevation of interleukin-22,
but not interleukin-21, in autoimmune experimental arthritis. Arthritis Rheum. 62:1043–50
127. Ziegler-Heitbrock L, Lötzerich M, Schaefer A, Werner T, Frankenberger M, Benkhart E. 2003. IFN-
α induces the human IL-10 gene by recruiting both IFN regulatory factor 1 and Stat3. J. Immunol.
171:285–90
128. Unterberger C, Staples KJ, Smallie T, Williams L, Foxwell B, et al. 2008. Role of STAT3 in
glucocorticoid-induced expression of the human IL-10 gene. Mol. Immunol. 45:3230–37
129. Xu J, Yang Y, Qiu G, Lal G, Wu Z, et al. 2009. c-Maf regulates IL-10 expression during Th17 polar-
ization. J. Immunol. 182:6226–36
130. Stumhofer JS, Laurence A, Wilson EH, Huang E, Tato CM, et al. 2006. Interleukin 27 negatively
regulates the development of interleukin 17-producing T helper cells during chronic inflammation of
the central nervous system. Nat. Immunol. 7:937–45
131. Mathur AN, Chang H-C, Zisoulis DG, Stritesky GL, Yu Q, et al. 2007. Stat3 and Stat4 direct develop-
ment of IL-17-secreting Th cells. J. Immunol. 178:4901–7
132. Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, et al. 2008. T helper 17 lineage differentiation
is programmed by orphan nuclear receptors RORα and RORγ. Immunity 28:29–39
133. Yang XO, Panopoulos AD, Nurieva R, Chang SH, Wang D, et al. 2007. STAT3 regulates cytokine-
mediated generation of inflammatory helper T cells. J. Biol. Chem. 282:9358–63
134. Rutz S, Janke M, Kassner N, Hohnstein T, Krueger M, Scheffold A. 2008. Notch regulates IL-10
production by T helper 1 cells. Proc. Natl. Acad. Sci. USA 105:3497–502
135. Kassner N, Krueger M, Yagita H, Dzionek A, Hutloff A, et al. 2010. Cutting edge: Plasmacytoid dendritic
cells induce IL-10 production in T cells via the Delta-like-4/Notch axis. J. Immunol. 184:550–54

100 Ouyang et al.

 IY29CH04-Ouyang ARI 4 February 2011 15:27

136. Mukherjee S, Schaller MA, Neupane R, Kunkel SL, Lukacs NW. 2009. Regulation of T cell activation
by Notch ligand, DLL4, promotes IL-17 production and Rorc activation. J. Immunol. 182:7381–88
137. Alam MS, Maekawa Y, Kitamura A, Tanigaki K, Yoshimoto T, et al. 2010. Notch signaling drives IL-22
secretion in CD4+ T cells by stimulating the aryl hydrocarbon receptor. Proc. Natl. Acad. Sci. USA
107:5943–48
138. Kim JI, Ho IC, Grusby MJ, Glimcher LH. 1999. The transcription factor c-Maf controls the production
of interleukin-4 but not other Th2 cytokines. Immunity 10:745–51
139. Ho IC, Lo D, Glimcher LH. 1998. c-maf promotes T helper cell type 2 (Th2) and attenuates Th1
differentiation by both interleukin 4-dependent and -independent mechanisms. J. Exp. Med. 188:1859–
66
140. Brightbill HD, Plevy SE, Modlin RL, Smale ST. 2000. A prominent role for Sp1 during
lipopolysaccharide-mediated induction of the IL-10 promoter in macrophages. J. Immunol. 164:1940–51
141. Tone M, Powell MJ, Tone Y, Thompson SA, Waldmann H. 2000. IL-10 gene expression is controlled
by the transcription factors Sp1 and Sp3. J. Immunol. 165:286–91
Annu. Rev. Immunol. 2011.29:71-109. Downloaded from www.annualreviews.org

142. Brenner S, Prösch S, Schenke-Layland K, Riese U, Gausmann U, Platzer C. 2003. cAMP-induced

interleukin-10 promoter activation depends on CCAAT/enhancer-binding protein expression and
monocytic differentiation. J. Biol. Chem. 278:5597–604
143. Liu Y-W, Tseng H-P, Chen L-C, Chen B-K, Chang W-C. 2003. Functional cooperation of simian virus
by University of Guelph on 05/31/12. For personal use only.

40 promoter factor 1 and CCAAT/enhancer-binding protein βand δin lipopolysaccharide-induced gene

activation of IL-10 in mouse macrophages. J. Immunol. 171:821–28
144. Csóka B, Németh ZH, Virág L, Gergely P, Leibovich SJ, et al. 2007. A2A adenosine receptors and
C/EBPβ are crucially required for IL-10 production by macrophages exposed to Escherichia coli. Blood
110:2685–95
145. Hu X, Paik PK, Chen J, Yarilina A, Kockeritz L, et al. 2006. IFN-γ suppresses IL-10 production and
synergizes with TLR2 by regulating GSK3 and CREB/AP-1 proteins. Immunity 24:563–74
146. Kremer KN, Kumar A, Hedin KE. 2007. Haplotype-independent costimulation of IL-10 secretion by
SDF-1/CXCL12 proceeds via AP-1 binding to the human IL-10 promoter. J. Immunol. 178:1581–88
147. Kanters E, Pasparakis M, Gijbels MJJ, Vergouwe MN, Partouns-Hendriks I, et al. 2003. Inhibition of
NF-κB activation in macrophages increases atherosclerosis in LDL receptor-deficient mice. J. Clin.
Investig. 112:1176–85
148. Platzer C, Fritsch E, Elsner T, Lehmann MH, Volk HD, Prosch S. 1999. Cyclic adenosine
monophosphate-responsive elements are involved in the transcriptional activation of the human IL-
10 gene in monocytic cells. Eur. J. Immunol. 29:3098–104
149. Wang Z, Sato H, Kusam S, Sehra S, Toney L, Dent A. 2005. Regulation of IL-10 gene expression in
Th2 cells by Jun proteins. J. Immunol. 174:2098–105
150. Yi AK, Yoon JG, Yeo SJ, Hong SC, English BK, Krieg AM. 2002. Role of mitogen-activated protein
kinases in CpG DNA-mediated IL-10 and IL-12 production: central role of extracellular signal-regulated
kinase in the negative feedback loop of the CpG DNA-mediated Th1 response. J. Immunol. 168:4711–20
151. Fuqua CF, Akomeah R, Price JO, Adunyah SE. 2008. Involvement of ERK-1/2 in IL-21-induced cytokine
production in leukemia cells and human monocytes. Cytokine 44:101–7
152. Owaki T, Asakawa M, Fukai F, Mizuguchi J, Yoshimoto T. 2006. IL-27 induces Th1 differentiation
via p38 MAPK/T-bet- and intercellular adhesion molecule-1/LFA-1/ERK1/2-dependent pathways.
J. Immunol. 177:7579–87
153. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, et al. 2006. The orphan nuclear receptor
RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126:1121–33
154. Satoh-Takayama N, Vosshenrich CA, Lesjean-Pottier S, Sawa S, Lochner M, et al. 2008. Microbial
flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune
defense. Immunity 29:958–70
155. Sanos SL, Bui VL, Mortha A, Oberle K, Heners C, et al. 2009. RORγt and commensal microflora
are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nat. Immunol.
10:83–91

www.annualreviews.org • IL-10 Family Cytokines in Immunity 101

 IY29CH04-Ouyang ARI 4 February 2011 15:27

156. Eberl G, Marmon S, Sunshine M-J, Rennert PD, Choi Y, Littman DR. 2004. An essential function for
the nuclear receptor RORγ(t) in the generation of fetal lymphoid tissue inducer cells. Nat. Immunol.
5:64–73
157. Trifari S, Kaplan CD, Tran EH, Crellin NK, Spits H. 2009. Identification of a human helper T cell
population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and
T(H)2 cells. Nat. Immunol. 10:864–71
158. Crellin NK, Trifari S, Kaplan CD, Cupedo T, Spits H. 2010. Human NKp44+ IL-22+ cells and LTi-
like cells constitute a stable RORC+ lineage distinct from conventional natural killer cells. J. Exp. Med.
207:281–90
159. Luci C, Reynders A, Ivanov II, Cognet C, Chiche L, Chasson L, et al. 2009. Influence of the transcription
factor RORγt on the development of NKp46+ cell populations in gut and skin. Nat. Immunol. 10:75–82
160. Veldhoen M, Hirota K, Christensen J, O’Garra A, Stockinger B. 2009. Natural agonists for aryl hydro-
carbon receptor in culture medium are essential for optimal differentiation of Th17 T cells. J. Exp. Med.
206:43–49
161. Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L, et al. 2008. The aryl hydrocarbon
Annu. Rev. Immunol. 2011.29:71-109. Downloaded from www.annualreviews.org

receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453:106–9

162. Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, et al. 2008. Control of T(reg) and T(H)17 cell
differentiation by the aryl hydrocarbon receptor. Nature 453:65–71
by University of Guelph on 05/31/12. For personal use only.

163. Kimura A, Naka T, Nohara K, Fujii-Kuriyama Y, Kishimoto T. 2008. Aryl hydrocarbon receptor reg-
ulates Stat1 activation and participates in the development of Th17 cells. Proc. Natl. Acad. Sci. USA
105:9721–26
164. Schraml BU, Hildner K, Ise W, Lee WL, Smith WA, et al. 2009. The AP-1 transcription factor Batf
controls T(H)17 differentiation. Nature 460:405–9
165. Brüstle A, Heink S, Huber M, Rosenplänter C, Stadelmann C, et al. 2007. The development of inflam-
matory T(H)-17 cells requires interferon-regulatory factor 4. Nat. Immunol. 8:958–66
166. Huber M, Brüstle A, Reinhard K, Guralnik A, Walter G, et al. 2008. IRF4 is essential for IL-21-mediated
induction, amplification, and stabilization of the Th17 phenotype. Proc. Natl. Acad. Sci. USA 105:20846–
51
167. Okamoto K, Iwai Y, Oh-Hora M, Yamamoto M, Morio T, et al. 2010. IκBζ regulates T(H)17 develop-
ment by cooperating with ROR nuclear receptors. Nature 464:1381–85
168. Boonstra A, Rajsbaum R, Holman M, Marques R, Asselin-Paturel C, et al. 2006. Macrophages and
myeloid dendritic cells, but not plasmacytoid dendritic cells, produce IL-10 in response to MyD88- and
TRIF-dependent TLR signals, and TLR-independent signals. J. Immunol. 177:7551–58
169. Edwards AD, Manickasingham SP, Spörri R, Diebold SS, Schulz O, et al. 2002. Microbial recognition via
Toll-like receptor-dependent and -independent pathways determines the cytokine response of murine
dendritic cell subsets to CD40 triggering. J. Immunol. 169:3652–60
170. Agrawal S, Agrawal A, Doughty B, Gerwitz A, Blenis J, et al. 2003. Cutting edge: different Toll-like
receptor agonists instruct dendritic cells to induce distinct Th responses via differential modulation of
extracellular signal-regulated kinase-mitogen-activated protein kinase and c-Fos. J. Immunol. 171:4984–
89
171. Rogers NC, Slack EC, Edwards AD, Nolte MA, Schulz O, et al. 2005. Syk-dependent cytokine induction
by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity 22:507–17
172. Dillon S, Agrawal A, Van Dyke T, Landreth G, McCauley L, et al. 2004. A Toll-like receptor 2 ligand
stimulates Th2 responses in vivo, via induction of extracellular signal-regulated kinase mitogen-activated
protein kinase and c-Fos in dendritic cells. J. Immunol. 172:4733–43
173. Geijtenbeek TBH, van Vliet SJ, Koppel EA, Sanchez-Hernandez M, Vandenbroucke-Grauls CMJE,
et al. 2003. Mycobacteria target DC-SIGN to suppress dendritic cell function. J. Exp. Med. 197:7–17
174. Fiorentino DF, Zlotnik A, Mosmann TR, Howard M, O’Garra A. 1991. IL-10 inhibits cytokine pro-
duction by activated macrophages. J. Immunol. 147:3815–22
175. Gerber JS, Mosser DM. 2001. Reversing lipopolysaccharide toxicity by ligating the macrophage Fcγ
receptors. J. Immunol. 166:6861–68
176. Chang EY, Guo B, Doyle SE, Cheng G. 2007. Cutting edge: involvement of the type I IFN production
and signaling pathway in lipopolysaccharide-induced IL-10 production. J. Immunol. 178:6705–9

102 Ouyang et al.

 IY29CH04-Ouyang ARI 4 February 2011 15:27

177. Netea MG, Sutmuller R, Hermann C, Van der Graaf CAA, Van der Meer JWM, et al. 2004. Toll-like
receptor 2 suppresses immunity against Candida albicans through induction of IL-10 and regulatory T
cells. J. Immunol. 172:3712–18
178. Higgins SC, Lavelle EC, McCann C, Keogh B, McNeela E, et al. 2003. Toll-like receptor 4-mediated
innate IL-10 activates antigen-specific regulatory T cells and confers resistance to Bordetella pertussis by
inhibiting inflammatory pathology. J. Immunol. 171:3119–27
179. Fujita S, Seino K-i, Sato K, Sato Y, Eizumi K, et al. 2006. Regulatory dendritic cells act as regulators of
acute lethal systemic inflammatory response. Blood 107:3656–64
180. Wang F, Lee E, Lowes MA, Haider AS, Fuentes-Duculan J, et al. 2006. Prominent production of IL-20
by CD68+ /CD11c+ myeloid-derived cells in psoriasis: gene regulation and cellular effects. J. Investig.
Dermatol. 126:1590–99
181. Yano S, Banno T, Walsh R, Blumenberg M. 2008. Transcriptional responses of human epidermal
keratinocytes to cytokine interleukin-1. J. Cell. Physiol. 214:1–13
182. Hunt DW, Boivin WA, Fairley LA, Jovanovic MM, King DE, et al. 2006. Ultraviolet B light stimulates
interleukin-20 expression by human epithelial keratinocytes. Photochem. Photobiol. 82:1292–300
Annu. Rev. Immunol. 2011.29:71-109. Downloaded from www.annualreviews.org

183. Wolk K, Witte E, Warszawska K, Schulze-Tanzil G, Witte K, et al. 2009. The Th17 cytokine IL-22
induces IL-20 production in keratinocytes: a novel immunological cascade with potential relevance in
psoriasis. Eur. J. Immunol. 39:3570–81
by University of Guelph on 05/31/12. For personal use only.

184. Huang F, Wachi S, Thai P, Loukoianov A, Tan KH, Forteza RM, Wu R. 2008. Potentiation of IL-19
expression in airway epithelia by IL-17A and IL-4/IL-13: important implications in asthma. J. Allergy
Clin. Immunol. 121:1415–21, 1421.e1–3
185. De Luca A, Zelante T, D’Angelo C, Zagarella S, Fallarino F, et al. 2010. IL-22 defines a novel immune
pathway of antifungal resistance. Mucosal Immunol. 3:361–73
186. Pickert G, Neufert C, Leppkes M, Zheng Y, Wittkopf N, et al. 2009. STAT3 links IL-22 signaling in
intestinal epithelial cells to mucosal wound healing. J. Exp. Med. 206:1465–72
187. Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Stevens S, Flavell RA. 2008. Innate and
adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity 29:947–57
188. Wolk K, Sabat R. 2006. Interleukin-22: a novel T- and NK-cell derived cytokine that regulates the
biology of tissue cells. Cytokine Growth Factor Rev. 17:367–80
189. Satoh-Takayama N, Vosshenrich CAJ, Lesjean-Pottier S, Sawa S, Lochner M, et al. 2008. Microbial
flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune
defense. Immunity 29:958–70
190. Satoh-Takayama N, Dumoutier L, Lesjean-Pottier S, Ribeiro VS, Mandelboim O, et al. 2009. The
natural cytotoxicity receptor NKp46 is dispensable for IL-22-mediated innate intestinal immune defense
against Citrobacter rodentium. J. Immunol. 183:6579–87
191. Vivier E, Spits H, Cupedo T. 2009. Interleukin-22-producing innate immune cells: new players in
mucosal immunity and tissue repair? Nat. Rev. Immunol. 9:229–34
192. Veiga-Fernandes H, Kioussis D, Coles M. 2010. Natural killer receptors: the burden of a name. J. Exp.
Med. 207:269–72
193. Satoh-Takayama N, Lesjean-Pottier S, Vieira P, Sawa S, Eberl G, et al. 2010. IL-7 and IL-15 in-
dependently program the differentiation of intestinal CD3-NKp46+ cell subsets from Id2-dependent
precursors. J. Exp. Med. 207:273–80
194. Sawa S, Cherrier M, Lochner M, Satoh-Takayama N, Fehling HJ, et al. 2010. Lineage relationship
analysis of RORγt+ innate lymphoid cells. Science 330:665–69
195. Wolk K, Kunz S, Witte E, Friedrich M, Asadullah K, Sabat R. 2004. IL-22 increases the innate immunity
of tissues. Immunity 21:241–54
196. Doyle SE, Schreckhise H, Khuu-Duong K, Henderson K, Rosler R, et al. 2006. Interleukin-29 uses a type
1 interferon-like program to promote antiviral responses in human hepatocytes. Hepatology 44:896–906
197. Marcello T, Grakoui A, Barba-Spaeth G, Machlin ES, Kotenko SV, et al. 2006. Interferons α and
λ inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics.
Gastroenterology 131:1887–98
198. Meager A, Visvalingam K, Dilger P, Bryan D, Wadhwa M. 2005. Biological activity of interleukins-28
and -29: comparison with type I interferons. Cytokine 31:109–18

www.annualreviews.org • IL-10 Family Cytokines in Immunity 103

 IY29CH04-Ouyang ARI 4 February 2011 15:27

199. Boniface K, Bernard FX, Garcia M, Gurney AL, Lecron JC, Morel F. 2005. IL-22 inhibits epidermal
differentiation and induces proinflammatory gene expression and migration of human keratinocytes.
J. Immunol. 174:3695–702
200. Aujla SJ, Chan YR, Zheng M, Fei M, Askew DJ, et al. 2008. IL-22 mediates mucosal host defense against
Gram-negative bacterial pneumonia. Nat. Med. 14:275–81
201. Liao SC, Cheng YC, Wang YC, Wang CW, Yang SM, et al. 2004. IL-19 induced Th2 cytokines and
was up-regulated in asthma patients. J. Immunol. 173:6712–18
202. Liao YC, Liang WG, Chen FW, Hsu JH, Yang JJ, Chang MS. 2002. IL-19 induces production of IL-6
and TNF-α and results in cell apoptosis through TNF-α. J. Immunol. 169:4288–97
203. Liu L, Ding C, Zeng W, Heuer JG, Tetreault JW, et al. 2003. Selective enhancement of multipotential
hematopoietic progenitors in vitro and in vivo by IL-20. Blood 102:3206–9
204. Wahl C, Müller W, Leithäuser F, Adler G, Oswald F, et al. 2009. IL-20 receptor 2 signaling down-
regulates antigen-specific T cell responses. J. Immunol. 182:802–10
205. Emdad L, Lebedeva IV, Su ZZ, Gupta P, Sauane M, et al. 2009. Historical perspective and recent
insights into our understanding of the molecular and biochemical basis of the antitumor properties of
Annu. Rev. Immunol. 2011.29:71-109. Downloaded from www.annualreviews.org

mda-7/IL-24. Cancer Biol. Ther. 8:391–400

206. Kreis S, Philippidou D, Margue C, Behrmann I. 2008. IL-24: a classic cytokine and/or a potential cure
for cancer? J. Cell. Mol. Med. 12:2505–10
by University of Guelph on 05/31/12. For personal use only.

207. Kreis S, Philippidou D, Margue C, Rolvering C, Haan C, et al. 2007. Recombinant interleukin-24 lacks
apoptosis-inducing properties in melanoma cells. PLoS ONE 2:e1300
208. Wolk K, Witte E, Wallace E, Docke WD, Kunz S, et al. 2006. IL-22 regulates the expression of genes
responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential
role in psoriasis. Eur. J. Immunol. 36:1309–23
209. Nagalakshmi ML, Rascle A, Zurawski S, Menon S, de Waal Malefyt R. 2004. Interleukin-22 activates
STAT3 and induces IL-10 by colon epithelial cells. Int. Immunopharmacol. 4:679–91
210. El Kasmi KC, Holst J, Coffre M, Mielke L, de Pauw A, et al. 2006. General nature of the STAT3-activated
anti-inflammatory response. J. Immunol. 177:7880–88
211. Savan R, McFarland AP, Reynolds DA, Feigenbaum L, Ramakrishnan K, et al. 2010. A novel role for
IL-22R1 as a driver of inflammation. Blood. In press
212. Mege JL, Meghari S, Honstettre A, Capo C, Raoult D. 2006. The two faces of interleukin 10 in human
infectious diseases. Lancet Infect. Dis. 6:557–69
213. Filippi CM, von Herrath MG. 2008. IL-10 and the resolution of infections. J. Pathol. 214:224–30
214. Ejrnaes M, Filippi CM, Martinic MM, Ling EM, Togher LM, et al. 2006. Resolution of a chronic viral
infection after interleukin-10 receptor blockade. J. Exp. Med. 203:2461–72
215. van der Kleij D, Latz E, Brouwers JFHM, Kruize YCM, Schmitz M, et al. 2002. A novel host-parasite
lipid cross-talk. Schistosomal lyso-phosphatidylserine activates Toll-like receptor 2 and affects immune
polarization. J. Biol. Chem. 277:48122–19
216. Jang S, Uematsu S, Akira S, Salgame P. 2004. IL-6 and IL-10 induction from dendritic cells in response
to Mycobacterium tuberculosis is predominantly dependent on TLR2-mediated recognition. J. Immunol.
173:3392–97
217. Sing A, Rost D, Tvardovskaia N, Roggenkamp A, Wiedemann A, et al. 2002. Yersinia V-antigen exploits
Toll-like receptor 2 and CD14 for interleukin 10-mediated immunosuppression. J. Exp. Med. 196:1017–
24
218. Gabrysová L, Nicolson K, Streeter HB, Verhagen J, Sabatos-Peyton CA, et al. 2009. Negative feedback
control of the autoimmune response through antigen-induced differentiation of IL-10-secreting Th1
cells. J. Exp. Med. 206:175–67
219. Jankovic D, Kullberg M, Feng C, Goldszmid R, Collazo C, et al. 2007. Conventional T-bet+ Foxp3− Th1
cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection.
J. Exp. Med. 204:273–83
220. Anderson C, Oukka M, Kuchroo V, Sacks D. 2007. CD4+ CD25− Foxp3− Th1 cells are the source of
IL-10-mediated immune suppression in chronic cutaneous leishmaniasis. J. Exp. Med. 204:285–97
221. Wu B, Huang C, Kato-Maeda M, Hopewell PC, Daley CL, et al. 2008. IL-24 modulates IFN-γ expres-
sion in patients with tuberculosis. Immunol. Lett. 117:57–62

104 Ouyang et al.

 IY29CH04-Ouyang ARI 4 February 2011 15:27

222. Ma Y, Chen H, Wang Q, Luo F, Yan J, Zhang XL. 2009. IL-24 protects against Salmonella typhimurium
infection by stimulating early neutrophil Th1 cytokine production, which in turn activates CD8+ T
cells. Eur. J. Immunol. 39:3357–68
223. Misse D, Yssel H, Trabattoni D, Oblet C, Lo Caputo S, et al. 2007. IL-22 participates in an innate
anti-HIV-1 host-resistance network through acute-phase protein induction. J. Immunol. 178:407–15
224. Levillayer F, Mas M, Levi-Acobas F, Brahic M, Bureau JF. 2007. Interleukin 22 is a candidate gene for
Tmevp3, a locus controlling Theiler’s virus-induced neurological diseases. Genetics 176:1835–44
225. Pagliaccetti NE, Eduardo R, Kleinstein SH, Mu XJ, Bandi P, Robek MD. 2008. Interleukin-29 functions
cooperatively with interferon to induce antiviral gene expression and inhibit hepatitis C virus replication.
J. Biol. Chem. 283:30079–89
226. Schulz SM, Kohler G, Schutze N, Knauer J, Straubinger RK, et al. 2008. Protective immunity to systemic
infection with attenuated Salmonella enterica serovar enteritidis in the absence of IL-12 is associated with
IL-23-dependent IL-22, but not IL-17. J. Immunol. 181:7891–901
227. Scriba TJ, Kalsdorf B, Abrahams DA, Isaacs F, Hofmeister J, et al. 2008. Distinct, specific IL-17- and
IL-22-producing CD4+ T cell subsets contribute to the human antimycobacterial immune response.
Annu. Rev. Immunol. 2011.29:71-109. Downloaded from www.annualreviews.org

J. Immunol. 180:1962–70
228. Pitta MG, Romano A, Cabantous S, Henri S, Hammad A, et al. 2009. IL-17 and IL-22 are associated
with protection against human kala azar caused by Leishmania donovani. J. Clin. Investig. 119:2379–87
by University of Guelph on 05/31/12. For personal use only.

229. Dhiman R, Indramohan M, Barnes PF, Nayak RC, Paidipally P, et al. 2009. IL-22 produced by human
NK cells inhibits growth of Mycobacterium tuberculosis by enhancing phagolysosomal fusion. J. Immunol.
183:6639–45
230. Sellge G, Magalhaes JG, Konradt C, Fritz JH, Salgado-Pabon W, et al. 2010. Th17 cells are the dominant
T cell subtype primed by Shigella flexneri mediating protective immunity. J. Immunol. 184:2076–85
231. Wilson MS, Feng CG, Barber DL, Yarovinsky F, Cheever AW, et al. 2010. Redundant and pathogenic
roles for IL-22 in mycobacterial, protozoan, and helminth infections. J. Immunol. 184:4378–90
232. Muñoz M, Heimesaat MM, Danker K, Struck D, Lohmann U, et al. 2009. Interleukin (IL)-23 mediates
Toxoplasma gondii-induced immunopathology in the gut via matrixmetalloproteinase-2 and IL-22 but
independent of IL-17. J. Exp. Med. 206:3047–59
233. Weber GF, Schlautkotter S, Kaiser-Moore S, Altmayr F, Holzmann B, Weighardt H. 2007. Inhibition
of interleukin-22 attenuates bacterial load and organ failure during acute polymicrobial sepsis. Infect.
Immun. 75:1690–97
234. Ashman RB, Fulurija A, Papadimitriou JM. 1999. Both CD4+ and CD8+ lymphocytes reduce the
severity of tissue lesions in murine systemic candidiasis, and CD4+ cells also demonstrate strain-specific
immunopathological effects. Microbiology 145(Pt. 7):1631–40
235. Tavares D, Ferreira P, Arala-Chaves M. 2000. Increased resistance to systemic candidiasis in athymic or
interleukin-10-depleted mice. J. Infect. Dis. 182:266–73
236. Acosta-Rodriguez EV, Rivino L, Geginat J, Jarrossay D, Gattorno M, et al. 2007. Surface phenotype and
antigenic specificity of human interleukin 17-producing T helper memory cells. Nat. Immunol. 8:639–46
237. Huang W, Na L, Fidel PL, Schwarzenberger P. 2004. Requirement of interleukin-17A for systemic
anti-Candida albicans host defense in mice. J. Infect. Dis. 190:624–31
238. Liu Y, Yang B, Zhou M, Li L, Zhou H, et al. 2009. Memory IL-22-producing CD4+ T cells specific for
Candida albicans are present in humans. Eur. J. Immunol. 39:1472–79
239. Eyerich K, Foerster S, Rombold S, Seidl HP, Behrendt H, et al. 2008. Patients with chronic mucocuta-
neous candidiasis exhibit reduced production of Th17-associated cytokines IL-17 and IL-22. J. Investig.
Dermatol. 128:2640–45
240. Kisand K, Boe Wolff AS, Podkrajsek KT, Tserel L, Link M, et al. 2010. Chronic mucocutaneous can-
didiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines.
J. Exp. Med. 207:299–308
241. Puel A, Döffinger R, Natividad A, Chrabieh M, Barcenas-Morales G, et al. 2010. Autoantibodies against
IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyen-
docrine syndrome type I. J. Exp. Med. 207:291–97
242. Conti HR, Shen F, Nayyar N, Stocum E, Sun JN, et al. 2009. Th17 cells and IL-17 receptor signaling
are essential for mucosal host defense against oral candidiasis. J. Exp. Med. 206:299–311

www.annualreviews.org • IL-10 Family Cytokines in Immunity 105

 IY29CH04-Ouyang ARI 4 February 2011 15:27

243. Miller DM, Klucher KM, Freeman JA, Hausman DF, Fontana D, Williams DE. 2009. Interferon lambda
as a potential new therapeutic for hepatitis C. Ann. N. Y. Acad. Sci. 1182:80–87
244. Ank N, Iversen MB, Bartholdy C, Staeheli P, Hartmann R, et al. 2008. An important role for type III
interferon (IFN-λ/IL-28) in TLR-induced antiviral activity. J. Immunol. 180:2474–85
245. Mordstein M, Kochs G, Dumoutier L, Renauld JC, Paludan SR, et al. 2008. Interferon-λ contributes
to innate immunity of mice against influenza A virus but not against hepatotropic viruses. PLoS Pathog.
4:e1000151
246. Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, et al. 2009. Genetic variation in IL28B predicts
hepatitis C treatment-induced viral clearance. Nature 461:399–401
247. Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, et al. 2009. Genetic variation in IL28B and spontaneous
clearance of hepatitis C virus. Nature 461:798–801
248. Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, et al. 2009. IL28B is associated with
response to chronic hepatitis C interferon-α and ribavirin therapy. Nat. Genet. 41:1100–4
249. Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, et al. 2009. Genome-wide association of
IL28B with response to pegylated interferon-α and ribavirin therapy for chronic hepatitis C. Nat. Genet.
Annu. Rev. Immunol. 2011.29:71-109. Downloaded from www.annualreviews.org

41:1105–9
250. Asadullah K, Sterry W, Volk HD. 2003. Interleukin-10 therapy—review of a new approach. Pharmacol.
Rev. 55:241–69
by University of Guelph on 05/31/12. For personal use only.

251. Xavier RJ, Podolsky DK. 2007. Unravelling the pathogenesis of inflammatory bowel disease. Nature
448:427–34
252. Hooper LV, Macpherson AJ. 2010. Immune adaptations that maintain homeostasis with the intestinal
microbiota. Nat. Rev. Immunol. 10:159–69
253. Artis D. 2008. Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis
in the gut. Nat. Rev. Immunol. 8:411–20
254. Braat H, Peppelenbosch MP, Hommes DW. 2003. Interleukin-10-based therapy for inflammatory bowel
disease. Expert. Opin. Biol. Ther. 3:725–31
255. Ouyang W, Valdez P. 2008. IL-22 in mucosal immunity. Mucosal Immunol. 1:335–38
256. Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W. 1993. Interleukin-10-deficient mice develop
chronic enterocolitis. Cell 75:263–74
257. Sellon RK, Tonkonogy S, Schultz M, Dieleman LA, Grenther W, et al. 1998. Resident enteric bacteria
are necessary for development of spontaneous colitis and immune system activation in interleukin-10-
deficient mice. Infect. Immun. 66:5224–31
258. Madsen KL, Doyle JS, Tavernini MM, Jewell LD, Rennie RP, Fedorak RN. 2000. Antibiotic therapy
attenuates colitis in interleukin 10 gene-deficient mice. Gastroenterology 118:1094–105
259. Davidson NJ, Leach MW, Fort MM, Thompson-Snipes L, Kuhn R, et al. 1996. T helper cell 1-type
CD4+ T cells, but not B cells, mediate colitis in interleukin 10-deficient mice. J. Exp. Med. 184:241–51
260. Aste-Amezaga M, Ma X, Sartori A, Trinchieri G. 1998. Molecular mechanisms of the induction of IL-12
and its inhibition by IL-10. J. Immunol. 160:5936–44
261. Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, et al. 2000. Novel p19 protein engages IL-12p40
to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity
13:715–25
262. Yen D, Cheung J, Scheerens H, Poulet F, McClanahan T, et al. 2006. IL-23 is essential for T cell-
mediated colitis and promotes inflammation via IL-17 and IL-6. J. Clin. Investig. 116:1310–16
263. Franke A, Balschun T, Karlsen TH, Sventoraityte J, Nikolaus S, et al. 2008. Sequence variants in IL10,
ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat. Genet. 40:1319–23
264. Mitsuyama K, Tomiyasu N, Takaki K, Masuda J, Yamasaki H, et al. 2006. Interleukin-10 in the patho-
physiology of inflammatory bowel disease: increased serum concentrations during the recovery phase.
Mediat. Inflamm. 2006:26875
265. Tomoyose M, Mitsuyama K, Ishida H, Toyonaga A, Tanikawa K. 1998. Role of interleukin-10 in a
murine model of dextran sulfate sodium-induced colitis. Scand. J. Gastroenterol. 33:435–40
266. Duchmann R, Schmitt E, Knolle P, Meyer zum Büschenfelde KH, Neurath M. 1996. Tolerance towards
resident intestinal flora in mice is abrogated in experimental colitis and restored by treatment with
interleukin-10 or antibodies to interleukin-12. Eur. J. Immunol. 26:934–38

106 Ouyang et al.

 IY29CH04-Ouyang ARI 4 February 2011 15:27

267. Tilg H, van Montfrans C, Van Den Ende A, Kaser A, van Deventer SJ, et al. 2002. Treatment of Crohn’s
disease with recombinant human interleukin 10 induces the proinflammatory cytokine interferon γ. Gut
50:191–95
268. Andoh A, Zhang Z, Inatomi O, Fujino S, Deguchi Y, et al. 2005. Interleukin-22, a member of the
IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts. Gastroenterology
129:969–84
269. Sekikawa A, Fukui H, Suzuki K, Karibe T, Fujii S, et al. 2010. Involvement of the IL-22/REG Iα axis
in ulcerative colitis. Lab. Investig. 90:496–505
270. Wolk K, Witte E, Hoffmann U, Doecke WD, Endesfelder S, et al. 2007. IL-22 induces
lipopolysaccharide-binding protein in hepatocytes: a potential systemic role of IL-22 in Crohn’s dis-
ease. J. Immunol. 178:5973–81
271. Kleinschek MA, Boniface K, Sadekova S, Grein J, Murphy EE, et al. 2009. Circulating and gut-resident
human Th17 cells express CD161 and promote intestinal inflammation. J. Exp. Med. 206:525–34
272. Schmechel S, Konrad A, Diegelmann J, Glas J, Wetzke M, et al. 2008. Linking genetic susceptibility
Annu. Rev. Immunol. 2011.29:71-109. Downloaded from www.annualreviews.org

to Crohn’s disease with Th17 cell function: IL-22 serum levels are increased in Crohn’s disease and
correlate with disease activity and IL23R genotype status. Inflamm. Bowel Dis. 14:204–12
273. Sugimoto K, Ogawa A, Mizoguchi E, Shimomura Y, Andoh A, et al. 2008. IL-22 ameliorates intestinal
inflammation in a mouse model of ulcerative colitis. J. Clin. Investig. 118:534–44
by University of Guelph on 05/31/12. For personal use only.

274. Neufert C, Pickert G, Zheng Y, Wittkopf N, Warntjen M, et al. 2010. Activation of epithelial STAT3
regulates intestinal homeostasis. Cell Cycle 9:652–55
275. Dambacher J, Beigel F, Zitzmann K, de Toni E, Göoke B, et al. 2008. The role of the novel Th17
cytokine IL-26 in intestinal inflammation. Gut 58:1207–17
276. Azuma YT, Matsuo Y, Kuwamura M, Yancopoulos GD, Valenzuela DM, et al. 2010. Interleukin-19
protects mice from innate-mediated colonic inflammation. Inflamm. Bowel Dis. 16:1017–28
277. Brand S, Beigel F, Olszak T, Zitzmann K, Eichhorst ST, et al. 2005. IL-28A and IL-29 mediate antipro-
liferative and antiviral signals in intestinal epithelial cells and murine CMV infection increases colonic
IL-28A expression. Am. J. Physiol. Gastrointest. Liver Physiol. 289:G960–68
278. Louis H, Le Moine O, Peny MO, Quertinmont E, Fokan D, et al. 1997. Production and role of
interleukin-10 in concanavalin A-induced hepatitis in mice. Hepatology 25:1382–89
279. Di Marco R, Xiang M, Zaccone P, Leonardi C, Franco S, et al. 1999. Concanavalin A-induced hepatitis in
mice is prevented by interleukin (IL)-10 and exacerbated by endogenous IL-10 deficiency. Autoimmunity
31:75–83
280. Radaeva S, Sun R, Pan HN, Hong F, Gao B. 2004. Interleukin 22 (IL-22) plays a protective role in T
cell-mediated murine hepatitis: IL-22 is a survival factor for hepatocytes via STAT3 activation. Hepatology
39:1332–42
281. Wahl C, Wegenka UM, Leithauser F, Schirmbeck R, Reimann J. 2009. IL-22-dependent attenuation of
T cell-dependent (ConA) hepatitis in herpes virus entry mediator deficiency. J. Immunol. 182:4521–28
282. Pan H, Hong F, Radaeva S, Gao B. 2004. Hydrodynamic gene delivery of interleukin-22 protects the
mouse liver from concanavalin A-, carbon tetrachloride-, and Fas ligand-induced injury via activation of
STAT3. Cell. Mol. Immunol. 1:43–49
283. Ren X, Hu B, Colletti LM. 2009. IL-22 is involved in liver regeneration after hepatectomy. Am. J.
Physiol. Gastrointest. Liver Physiol. 298:G74–80
284. Yang L, Zhang Y, Wang L, Fan F, Zhu L, et al. 2010. Amelioration of high fat diet induced liver
lipogenesis and hepatic steatosis by interleukin-22. J. Hepatol. 53(2):339–47
285. Wegenka UM, Dikopoulos N, Reimann J, Adler G, Wahl C. 2007. The murine liver is a potential
target organ for IL-19, IL-20 and IL-24: type I interferons and LPS regulate the expression of IL-20R2.
J. Hepatol. 46:257–65
286. Lowes MA, Bowcock AM, Krueger JG. 2007. Pathogenesis and therapy of psoriasis. Nature 445:866–73
287. Rømer J, Hasselager E, Nørby PL, Steiniche T, Thorn Clausen J, Kragballe K. 2003. Epidermal over-
expression of interleukin-19 and -20 mRNA in psoriatic skin disappears after short-term treatment with
cyclosporine a or calcipotriol. J. Investig. Dermatol. 121:1306–11

www.annualreviews.org • IL-10 Family Cytokines in Immunity 107

 IY29CH04-Ouyang ARI 4 February 2011 15:27

288. Otkjaer K, Kragballe K, Funding AT, Clausen JT, Noerby PL, et al. 2005. The dynamics of gene
expression of interleukin-19 and interleukin-20 and their receptors in psoriasis. Br. J. Dermatol. 153:911–
18
289. Tohyama M, Hanakawa Y, Shirakata Y, Dai X, Yang L, et al. 2009. IL-17 and IL-22 mediate IL-20
subfamily cytokine production in cultured keratinocytes via increased IL-22 receptor expression. Eur. J.
Immunol. 39:2779–88
290. Boniface K, Guignouard E, Pedretti N, Garcia M, Delwail A, et al. 2007. A role for T cell-derived
interleukin 22 in psoriatic skin inflammation. Clin. Exp. Immunol. 150:407–15
291. Pene J, Chevalier S, Preisser L, Venereau E, Guilleux MH, et al. 2008. Chronically inflamed human
tissues are infiltrated by highly differentiated Th17 lymphocytes. J. Immunol. 180:7423–30
292. Kagami S, Rizzo HL, Lee JJ, Koguchi Y, Blauvelt A. 2009. Circulating Th17, Th22, and Th1 cells are
increased in psoriasis. J. Investig. Dermatol. 130:1373–83
293. Kunz S, Wolk K, Witte E, Witte K, Doecke WD, et al. 2006. Interleukin (IL)-19, IL-20 and IL-24 are
produced by and act on keratinocytes and are distinct from classical ILs. Exp. Dermatol. 15:991–1004
Annu. Rev. Immunol. 2011.29:71-109. Downloaded from www.annualreviews.org

294. Li W, Danilenko DM, Bunting S, Ganesan R, Sa S, et al. 2009. The serine protease marapsin is expressed
in stratified squamous epithelia and is up-regulated in the hyperproliferative epidermis of psoriasis and
regenerating wounds. J. Biol. Chem. 284:218–28
295. Guilloteau K, Paris I, Pedretti N, Boniface K, Juchaux F, et al. 2010. Skin inflammation induced by the
by University of Guelph on 05/31/12. For personal use only.

synergistic action of IL-17A, IL-22, oncostatin M, IL-1α, and TNF-α recapitulates some features of
psoriasis. J. Immunol. 184:5263–70
296. Gudjonsson JE, Ding J, Johnston A, Tejasvi T, Guzman AM, et al. 2010. Assessment of the psori-
atic transcriptome in a large sample: additional regulated genes and comparisons with in vitro models.
J. Investig. Dermatol. 130:1829–40
297. He M, Liang P. 2010. IL-24 transgenic mice: in vivo evidence of overlapping functions for IL-20, IL-22,
and IL-24 in the epidermis. J. Immunol. 184:1793–98
298. Wolk K, Haugen HS, Xu W, Witte E, Waggie K, et al. 2009. IL-22 and IL-20 are key mediators of the
epidermal alterations in psoriasis while IL-17 and IFN-γ are not. J. Mol. Med. 87:523–36
299. Kingo K, Koks S, Nikopensius T, Silm H, Vasar E. 2004. Polymorphisms in the interleukin-20 gene:
relationships to plaque-type psoriasis. Genes Immun. 5:117–21
300. Koks S, Kingo K, Ratsep R, Karelson M, Silm H, Vasar E. 2004. Combined haplotype analysis of the
interleukin-19 and -20 genes: relationship to plaque-type psoriasis. Genes Immun. 5:662–67
301. Koks S, Kingo K, Vabrit K, Ratsep R, Karelson M, et al. 2005. Possible relations between the polymor-
phisms of the cytokines IL-19, IL-20 and IL-24 and plaque-type psoriasis. Genes Immun. 6:407–15
302. Capon F, Di Meglio P, Szaub J, Prescott NJ, Dunster C, et al. 2007. Sequence variants in the genes
for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis. Hum.
Genet. 122:201–6
303. Kopp T, Lenz P, Bello-Fernandez C, Kastelein RA, Kupper TS, Stingl G. 2003. IL-23 production
by cosecretion of endogenous p19 and transgenic p40 in keratin 14/p40 transgenic mice: evidence for
enhanced cutaneous immunity. J. Immunol. 170:5438–44
304. Chan JR, Blumenschein W, Murphy E, Diveu C, Wiekowski M, et al. 2006. IL-23 stimulates epidermal
hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis.
J. Exp. Med. 203:2577–87
305. Ma HL, Liang S, Li J, Napierata L, Brown T, et al. 2008. IL-22 is required for Th17 cell-mediated
pathology in a mouse model of psoriasis-like skin inflammation. J. Clin. Investig. 118:597–607
306. Stenderup K, Rosada C, Worsaae A, Dagnaes-Hansen F, Steiniche T, et al. 2009. Interleukin-20 plays a
critical role in maintenance and development of psoriasis in the human xenograft transplantation model.
Br. J. Dermatol. 160:284–96
307. Krueger GG, Langley RG, Leonardi C, Yeilding N, Guzzo C, et al. 2007. A human interleukin-12/23
monoclonal antibody for the treatment of psoriasis. N. Engl. J. Med. 356(6):580–92
308. Alanärä T, Karstila K, Moilanen T, Silvennoinen O, Isomäki P. 2010. Expression of IL-10 family cy-
tokines in rheumatoid arthritis: elevated levels of IL-19 in the joints. Scand. J. Rheumatol. 39:118–26

108 Ouyang et al.

 IY29CH04-Ouyang ARI 4 February 2011 15:27

309. Kragstrup TW, Otkjaer K, Holm C, Jørgensen A, Hokland M, et al. 2008. The expression of IL-20 and
IL-24 and their shared receptors are increased in rheumatoid arthritis and spondyloarthropathy. Cytokine
41:16–23
310. Sakurai N, Kuroiwa T, Ikeuchi H, Hiramatsu N, Maeshima A, et al. 2008. Expression of IL-19 and its
receptors in RA: potential role for synovial hyperplasia formation. Rheumatology 47:815–20
311. Ikeuchi H, Kuroiwa T, Hiramatsu N, Kaneko Y, Hiromura K, et al. 2005. Expression of interleukin-22
in rheumatoid arthritis: potential role as a proinflammatory cytokine. Arthritis Rheum. 52:1037–46
312. Shen H, Goodall JC, Hill Gaston JS. 2009. Frequency and phenotype of peripheral blood Th17 cells in
ankylosing spondylitis and rheumatoid arthritis. Arthritis Rheum. 60:1647–56
313. Hsu YH, Li HH, Hsieh MY, Liu MF, Huang KY, et al. 2006. Function of interleukin-20 as a proin-
flammatory molecule in rheumatoid and experimental arthritis. Arthritis Rheum. 54:2722–33
314. Geboes L, Dumoutier L, Kelchtermans H, Schurgers E, Mitera T, et al. 2009. Proinflammatory role
of the Th17 cytokine interleukin-22 in collagen-induced arthritis in C57BL/6 mice. Arthritis Rheum.
60:390–95
315. Li HH, Cheng HH, Sun KH, Wei CC, Li CF, et al. 2008. Interleukin-20 targets renal mesangial cells
Annu. Rev. Immunol. 2011.29:71-109. Downloaded from www.annualreviews.org

and is associated with lupus nephritis. Clin. Immunol. 129:277–85

316. Cheng F, Guo Z, Xu H, Yan D, Li Q. 2009. Decreased plasma IL22 levels, but not increased IL17 and
IL23 levels, correlate with disease activity in patients with systemic lupus erythematosus. Ann. Rheum.
by University of Guelph on 05/31/12. For personal use only.

Dis. 68:604–6
317. Kebir H, Kreymborg K, Ifergan I, Dodelet-Devillers A, Cayrol R, et al. 2007. Human TH17 lymphocytes
promote blood-brain barrier disruption and central nervous system inflammation. Nat. Med. 13:1173–75
318. Schnyder B, Lima C, Schnyder-Candrian S. 2010. Interleukin-22 is a negative regulator of the allergic
response. Cytokine 50:220–27
319. Di Stefano A, Caramori G, Gnemmi I, Contoli M, Vicari C, et al. 2009. T helper type 17-related cytokine
expression is increased in the bronchial mucosa of stable chronic obstructive pulmonary disease patients.
Clin. Exp. Immunol. 157:316–24
320. Chang H, Hanawa H, Liu H, Yoshida T, Hayashi M, et al. 2006. Hydrodynamic-based delivery of an
interleukin-22-Ig fusion gene ameliorates experimental autoimmune myocarditis in rats. J. Immunol.
177:3635–43
321. Kapessidou P, Poulin L, Dumoutier L, Goldman M, Renauld JC, Braun MY. 2008. Interleukin-22
deficiency accelerates the rejection of full major histocompatibility complex-disparate heart allografts.
Transplant. Proc. 40:1593–97
322. Barrett JC, Clayton DG, Concannon P, Akolkar B, Cooper JD, et al. 2009. Genome-wide association
study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat. Genet. 41:703–7

www.annualreviews.org • IL-10 Family Cytokines in Immunity 109

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Annual Review of
Immunology

Contents Volume 29, 2011

Innate Antifungal Immunity: The Key Role of Phagocytes

Gordon D. Brown p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
Stromal Cell–Immune Cell Interactions
Annu. Rev. Immunol. 2011.29:71-109. Downloaded from www.annualreviews.org

Ramon Roozendaal and Reina E. Mebius p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p23

Nonredundant Roles of Basophils in Immunity
by University of Guelph on 05/31/12. For personal use only.

Hajime Karasuyama, Kaori Mukai, Kazushige Obata, Yusuke Tsujimura,

and Takeshi Wada p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p45
Regulation and Functions of IL-10 Family of Cytokines
in Inflammation and Disease
Wenjun Ouyang, Sascha Rutz, Natasha K. Crellin, Patricia A. Valdez,
and Sarah G. Hymowitz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p71
Prevention and Treatment of Papillomavirus-Related Cancers
Through Immunization
Ian H. Frazer, Graham R. Leggatt, and Stephen R. Mattarollo p p p p p p p p p p p p p p p p p p p p p p p p 111
HMGB1 Is a Therapeutic Target for Sterile Inflammation and Infection
Ulf Andersson and Kevin J. Tracey p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 139
Plasmacytoid Dendritic Cells: Recent Progress and Open Questions
Boris Reizis, Anna Bunin, Hiyaa S. Ghosh, Kanako L. Lewis, and Vanja Sisirak p p p p p 163
Nucleic Acid Recognition by the Innate Immune System
Roman Barbalat, Sarah E. Ewald, Maria L. Mouchess, and Gregory M. Barton p p p p p p 185
Trafficking of B Cell Antigen in Lymph Nodes
Santiago F. Gonzalez, Søren E. Degn, Lisa A. Pitcher, Matthew Woodruff,
Balthasar A. Heesters, and Michael C. Carroll p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 215
Natural Innate and Adaptive Immunity to Cancer
Matthew D. Vesely, Michael H. Kershaw, Robert D. Schreiber,
and Mark J. Smyth p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 235
Immunoglobulin Responses at the Mucosal Interface
Andrea Cerutti, Kang Chen, and Alejo Chorny p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 273
HLA/KIR Restraint of HIV: Surviving the Fittest
Arman A. Bashirova, Rasmi Thomas, and Mary Carrington p p p p p p p p p p p p p p p p p p p p p p p p p p p 295

v
 IY29-Frontmatter ARI 4 February 2011 21:56

Mechanisms that Promote and Suppress Chromosomal Translocations

in Lymphocytes
Monica Gostissa, Frederick W. Alt, and Roberto Chiarle p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 319
Pathogenesis and Host Control of Gammaherpesviruses: Lessons from
the Mouse
Erik Barton, Pratyusha Mandal, and Samuel H. Speck p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 351
Genetic Defects in Severe Congenital Neutropenia: Emerging Insights into
Life and Death of Human Neutrophil Granulocytes
Christoph Klein p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 399
Inflammatory Mechanisms in Obesity
Margaret F. Gregor and Gökhan S. Hotamisligil p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 415
Annu. Rev. Immunol. 2011.29:71-109. Downloaded from www.annualreviews.org

Human TLRs and IL-1Rs in Host Defense: Natural Insights

from Evolutionary, Epidemiological, and Clinical Genetics
Jean-Laurent Casanova, Laurent Abel, and Lluis Quintana-Murci p p p p p p p p p p p p p p p p p p p p 447
by University of Guelph on 05/31/12. For personal use only.

Integration of Genetic and Immunological Insights into a Model of Celiac

Disease Pathogenesis
Valérie Abadie, Ludvig M. Sollid, Luis B. Barreiro, and Bana Jabri p p p p p p p p p p p p p p p p p p p 493
Systems Biology in Immunology: A Computational Modeling Perspective
Ronald N. Germain, Martin Meier-Schellersheim, Aleksandra Nita-Lazar,
and Iain D.C. Fraser p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 527
Immune Response to Dengue Virus and Prospects for a Vaccine
Brian R. Murphy and Stephen S. Whitehead p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 587
Follicular Helper CD4 T Cells (TFH )
Shane Crotty p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 621
SLAM Family Receptors and SAP Adaptors in Immunity
Jennifer L. Cannons, Stuart G. Tangye, and Pamela L. Schwartzberg p p p p p p p p p p p p p p p p p 665
The Inflammasome NLRs in Immunity, Inflammation,
and Associated Diseases
Beckley K. Davis, Haitao Wen, and Jenny P.-Y. Ting p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 707

Indexes

Cumulative Index of Contributing Authors, Volumes 19–29 p p p p p p p p p p p p p p p p p p p p p p p p p p p 737

Cumulative Index of Chapter Titles, Volumes 19–29 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 744

Errata

An online log of corrections to Annual Review of Immunology articles may be found at

http://immunol.annualreviews.org/errata.shtml

vi Contents