23

Cytokines
IAIN B. MCINNES

KEY POINTS
Cytokines are peptides that have a fundamental role in
communication within the immune system and in allowing the
immune system and host tissues cells to exchange information.
Cytokines act via binding to a cognate receptor which in turn
sends a signal to the recipient cell that leads to a change in
function or phenotype of that cell. Such signal cascades are
complex and allow the intebration of a variety of cytokine
signals to one cell at any given time.
Cytokines exist in broad families that are structurally
related but may contain rather diverse function, e.g., TNF/TNF
receptor superfamily, IL-1 superfamily.
Cytokine targeting has proved efcacious in a variety of
rheumatic diseases, particularly for TNF many more cytokines are currently under investigation as therapeutic targets,
or as therapeutic entities in their own right.

Immune function depends on the biologic activities of

numerous small glycoprotein messengers, termed cytokines.
Originally discovered and defined on the basis of their functional activities, cytokines are now designated primarily
by structure. Typically, cytokines exhibit broad functional
activities that mediate not only effector and regulatory
immune function, but also wider effects across a range of
tissues and biologic systems. As such, cytokines play a role
not only in host defense, but also in a variety of normal
physiologic and metabolic processes. The human genome
project has facilitated discovery of numerous cytokines,
posing considerable challenges in resolving their respective
and synergistic functions in complex tissues in health and
disease. Such understanding is, however, essential with the
advent of cytokine-targeting therapies in the clinic. This
chapter reviews general features of cytokine biology and the
cellular and molecular networks within which cytokines
operate; the focus is on the effector functions of cytokines that are important in chronic inflammation and in
rheumatic diseases.

CLASSIFICATION OF CYTOKINES
In the absence of a unified classification system, cytokines
are variously identified by numeric order of discovery
(currently interleukin [IL]-1 through IL-35), by a given
functional activity (e.g., tumor necrosis factor [TNF], granulocyte colony-stimulating factor), by kinetic or functional
role in inflammatory responses (early or late, innate or adaptive, proinflammatory or anti-inflammatory) (Fig. 23-1), by
primary cell of origin (monokine = monocyte derivation;
lymphokine = lymphocyte derivation), and, more recently,
by structural homologies shared with related molecules.

Superfamilies of cytokines share sequence similarity and

exhibit homology and some promiscuity in their reciprocal
receptor systems. They do not exhibit functional similarity.
Cytokine superfamilies also contain important regulatory
cell membrane receptor-ligand pairs, reflecting evolutionary pressures that use common structural motifs in diverse
immune functions in higher mammals. The TNF/TNF
receptor superfamily1 contains immunoregulatory cytokines,
including TNF-; lymphotoxins; and cellular ligands, such as
CD40L, which mediates B cell and T cell activation, and FasL
(CD95), which promotes apoptosis. Similarly, the IL-1/IL-1
receptor superfamily2 contains cytokines, including IL-1,
IL-1, IL-receptor antagonist, IL-18, and IL-33, which
mediate physiologic and host-defense function, but this
family also includes the Toll-like receptors, a series of mammalian pattern-recognition molecules with a crucial role in
recognition of microbial species early in innate responses.

ASSESSING CYTOKINE FUNCTION

IN VITRO AND IN VIVO
Although originally identified by bioactivity and quantified
by bioassay, most cytokines are now identified via homologous
receptor binding or sequence homology in gene databases.
They are quantified in biologic solutions by enzyme-linked
immunosorbent assay or by multiplex technology, the latter
allowing many (>25) cytokines to be measured in single,
small sample volumes (approximately 20 L). Function is
thereafter assessed by identification of the cellular source of
cytokine, determination of native stimuli, characterization
of receptor distribution, and determination of function in
target cells. Experimental in vivo models use the addition
of neutralizing cytokine-specific antibodies or soluble receptors (often as fragment crystallizable fusion or pegylated
proteins to enhance half-life and modulate functional interaction with leukocytes) to modulate cytokine function.
Genetically modified knockout mice (cytokine or receptor
rendered deficient by embryonic stem cell technology) or
transgenic mice (tissue/cell lineage-specific overexpression)
have proved particularly useful. Conditional gene-targeting
approaches (e.g., using the cre system) facilitate circumvention of embryonic lethal deficiencies or allow kinetic evaluation of the relative contribution of a cytokine throughout a
response. Cytokine function is assessed in vitro in primary or
transformed cell lines stimulated in the presence or absence
of recombinant cytokine or specific anticytokine antibody
or soluble receptor.
This general approach has proved crucial in rheumatic disease research. Studies in which cytokine addition and neutralization occurs in synovial tissue explants
or disaggregated cell populations, chondrocyte explants,
367

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MCINNES

1
Stimulus
e.g.,
Microbe
Cell contact
DNA
Cytokine
Antibody/IC
Sheer stress
Pressure

CYTOKINES

4
2

Effector
function

Cytokine
Receptor

Figure 23-1 Overview of cytokine regulatory function. Numerous and

diverse stimuli (1) promote cytokine expression arising either from novel
gene expression (2) or from activation of preformed cytokine (3). Cytokine
proteins are thereafter expressed in the cytosol, on the cell membrane,
or in soluble form in the extracellular environment (4). Cytokines bind
to reciprocal receptors that reside either on the membrane of a target
cell or in the soluble phase (5). Membrane receptors, on cytokine ligation,
signal to the recipient cell nucleus (6) and drive novel gene expression
to promote effector function. Each phase of cytokine function offers rich
therapeutic potential. IC, immune complexes.

bone culture models, skin, and renal tissue explants and

lines all have proved informative. Ex vivo methodologies
now include intracellular fluorescence activated cell sorter
methods, confocal and laser scanning microscopy, and
quantitative histologic evaluation using automated image
analysis. Such modalities, particularly when employed
in human therapeutic cytokine neutralization studies in
which inflammatory tissues are obtained through therapy,
are considerably advancing the understanding of basic and
pathogenetic cytokine function. Analysis of synovial biopsy
specimens obtained during infliximab, rituximab, IL-1Ra,
IL-10, and interferon (IFN)- administration in rheumatoid
arthritis provides the strongest evidence for the success of
this approach.3,4

CYTOKINE RECEPTORS
Cytokine receptors exist in structurally related superfamilies
and comprise high-affinity molecular signaling complexes
that facilitate cytokine-mediated communication. Such
complexes often include heterodimeric or heterotrimeric
structures that use unique, cytokine-specific recognition
receptors together with common receptor chains shared
across a cytokine superfamily. Examples include the use
of the common chain receptor by IL-2, IL-4, IL-7, IL-9,
IL-15, IL-21, and glycoprotein 130 (gp130) by members of
the IL-6 family.5,6 Alternatively, distinct receptors may use
shared signaling domains. Homologous death domains are
found in many TNF-receptor family members. Similarly,
the IL-1 signaling domain is common to not only IL-1R,
but also to other IL-1R superfamily members, including
IL-18R, ST2, and the Toll-like receptors.2 Signaling pathways dependent on these are discussed in detail elsewhere.
It has been recognized more recently that unrelated cytokine receptor systems exhibit close cross-communication
on the cell membrane, allowing a cell to integrate a variety
of external stimuli to optimize signaling pathways and the
cellular response in real-time in a changing environment.
Although best elucidated in the epidermal growth factor
receptor system, this also has been identified for members of
the common chain signaling family.

Cytokine receptors can operate via several mechanisms.

Membrane receptors, with intracellular signaling domains
intact, can transmit signals to the target cell nucleus after
soluble cytokine binding and promote effector function.
Membrane receptors may bind cell membrane cytokines
facilitating cross-talk between adjacent cells. Membranebound and soluble cytokines may promote distinct receptor
function. TNF- binds TNF-RI and TNF-RII with similar
affinity, but it has a slower rate of dissociation from TNF-RI.
Soluble TNF- may dissociate rapidly from TNF-RII to
bind TNF-RI, promoting preferential signaling by the latter
(ligand passing).1 In contrast, during cell-cell contact, stable TNF-/TNF-RI and TNF-/TNF-RII complexes form,
allowing for differential signaling contribution by TNF-RI
and TNF-RII. Cytokine receptor/cytokine complexes also
may operate in trans, whereby component parts of the
ligand-receptor complex are derived from adjacent cells.
IL-15/IL-15R complexed on one cell may bind IL-15R/
on another.7 Receptors also exist in soluble form, derived
either from alternative mRNA processing to generate
receptor-lacking transmembrane or intracellular domains
or from enzymatic cleavage of receptor from the cell surface (e.g., sTNF-R, sIL-1R1). Soluble receptors may act to
antagonize cytokine function, regulating responses. Soluble
receptors also may preform complexes with cytokine to promote subsequent ligand-receptor assembly on the target cell
membrane and enhance function. Soluble receptors can
deliver cytokine to the cell membrane via ligand passing.
Finally, it is now recognized that some cytokines with the
capacity to be retained in the membrane may themselves
function as signaling molecules (reverse signaling).

REGULATION OF CYTOKINE EXPRESSION

Cytokines are synthesized in the Golgi and may traffic
through the endoplasmic reticulum to be released as soluble
mediators, or they may remain membrane bound, or they
may be processed into cytosolic forms that can traffic intracellularly, even returning to the nucleus where they can act
as transcriptional regulators. Cytokines mediate autocrine
function either through release or membrane expression
and immediate receptor ligation on the source cell or intracellularly within the source cell. Alternatively, cytokines
operate in a paracrine manner, allowing cellular communication beyond that facilitated by local cell-cell contact. The
distance and kinetics for effective function may be limited,8
however, by numerous factors, including physicochemical
considerations of the peptide structure itself, extracellular
matrix binding (e.g., to heparan sulfate), enzymatic degradation (e.g., serine protease degradation of IL-18), or the
presence of soluble receptors (e.g., TNF-/soluble TNF-RI
and TNF-RII, IL-2/soluble IL-2R) or novel cytokinebinding proteins (e.g., IL-18/IL-18 binding protein) in the
inflammatory milieu.
Numerous factors promote cytokine expression in vivo
(Fig. 23-1), including cell-cell contact, immune complexes/
autoantibodies, local complement activation, microbial
species and their soluble products, reactive oxygen and
nitrogen intermediates, trauma, sheer stress, ischemia,
radiation, ultraviolet light, extracellular matrix components,
DNA (mammalian or microbial), heat shock proteins, and
cytokines themselves in autocrine loops. Commonly used in

PART 3

Hierarchy

Late
Early
Kinetics
Anti

Inflammatory
potential

Pro

Figure 23-2 Placing cytokines in functional context. Cytokines often

exhibit pleiotropic functions that vary throughout an immune response
and according to the nature of a stimulus. Cytokines could be envisaged
at one point in three-dimensional space, representing their hierarchic
capacity to contribute to an inammatory lesion over time. A given cytokine might have early proinammatory function but late, net anti-inammatory function within an evolving immune response. Similarly, at an
early stage, a cytokine might function atop a hierarchy, but later function
primarily as an effector downstream moiety. Cytokines may have roles in
innate and acquired responses that are discrete. A cytokine might have
distinct functions in different tissues and in response to different stimuli.
This has important implications for predicting the effect of cytokine targeting in vivo.

vitro stimuli include many of these and chemical entities,

including phorbol esters, calcium ionophores, lectins (e.g.,
phytohemagglutinin), and receptor-specific antibodies such
as anti-CD3 and anti-CD28 for T cell activation or antiimmunoglobulin and anti-CD40 for B cells.
Cytokine regulation within the cell can be usefully considered at several levels. Transcriptional regulation depends
on the recruitment of discrete transcription factors to the
cytokine promoter region. Transcription factor binding
allows for numerous signal pathways to regulate cytokine
expression across a range of stimuli. Several transcription
factors (e.g., nuclear factor B [NFB], activator protein-1
[AP-1], nuclear factor of activated T cell) are crucial in cytokine production. Inhibition of NFB activity using either
chemical inhibitors or adenoviral delivery of regulatory peptides leads to amelioration of inflammatory synovitis in vivo
and in vitro.9 Sequence polymorphism within cytokine promoters offers potential for differential cytokine expression
between individuals that could confer selective advantage
against infection, but also could increase susceptibility to, or
progression of, autoimmunity. This is best exemplified in the
TNF- and IL-1 promoters.10,11 Single nucleotide polymorphisms in the TNF- promoter region (e.g., 308) are associated with altered TNF- release on leukocyte stimulation
in vitro. Similarly, homozygotes for the A2 allele at +3954 in
the IL-1 gene produce more IL-1 with lipopolysaccharide
stimulation. Polymorphisms also exist in the IL-1Ra gene,
rendering the functional significance of individual single
nucleotide polymorphisms on IL-1 protein release difficult
to interpret. In general, the net effect of haplotypes may be
more important at the functional level, particularly when
their relevance to disease entities is considered.
Post-transcriptional regulation is important in determining longevity of cytokine expression. This regulation
may operate by promoting translational initiation, mRNA

EFFECTOR MECHANISMS IN AUTOIMMUNITY AND INFLAMMATION

369

stability, and polyadenylation. AU-rich elements (AREs)

within the 5 or 3 untranslated regions (UTRs) of cytokine
mRNA are crucial for stability; 3 UTR AREs downregulate
TNF expression such that transgenic knockin mice that lack
TNF- AREs develop spontaneous inflammatory arthritis
and bowel disease.12 Regulatory proteins bind AREs to mediate such effects. HuR and AUF1 exert opposing effects, stabilizing and destabilizing ARE-containing transcripts.13 TIA-1
and TIAR have been identified as RNA recognition motif
family members14 that function as translational silencers.
Macrophages from TIA-1-deficient macrophages produce
excess TNF-, whereas TIA-1-deficient lymphocytes exhibit
normal TNF- release, suggesting distinctions in mRNA
regulation in discrete cell types.15 Alternatively, cytokines
may generate stable mRNA a priori to facilitate subsequent
rapid response in tissues. IL-15 mRNA 5 UTR contains 12
AUG triplets that significantly reduce the efficiency of IL-15
translation. Deletion of this sequence permits IL-15 secretion. IL-15 mRNA can produce a 48-amino acid signal peptide that allows IL-15 release and a shorter 21-amino acid
signal peptide that targets intracellular distribution. IL-15
forms thus generated exhibit discrete functions.16
Post-translational regulation also modulates cytokine
expression via several mechanisms. Patterns of glycosylation are important for cytokine function and may regulate intracellular trafficking.16 Modified leader sequences
may alter intracellular trafficking of cytokines. Some cytokines are translated without functional leader sequences.
Their secretion depends on nonconventional secretory
pathways that are so far poorly understood. IL-1 employs
a purine receptordependent pathway (P2X7) for cellular
release.17 Enzymatic activation of cytokines is common,
whereby nonfunctional promolecules are cleaved to generate functional subunits. Examples include the cleavage
by caspase 1 of pro-IL-1 to generate active IL-1 and,
similarly, of pro-IL-18 to generate an active 18-kD
species.18 This is an organized process sequentially and
in the orientation within the cell. IL-1 processing occurs
in a protein complex within the cytosol termed the
inflammasome.
Alternative processing pathways for cytokines include
the serine proteases, proteinase 3 and elastase, and adamolysin family members. Enzyme cleavage pathways operate within and outside cells, providing for extracellular
cytokine activation. Similarly, cell membrane enzymes
serve to cleave membrane-expressed cytokine. Members
of the adamolysin family regulate TNF- release; TNF-converting enzyme cleaves and mediates the release of
TNF- and its receptors.19 Extensive molecular machinery
exists to regulate tightly not only the production and stability of cytokine mRNA, but also its translation and cellular
expression and distribution. At each level, opportunities
exist for intervention and therapeutic cytokine modulation.

EFFECTOR FUNCTION OF CYTOKINES

Cytokines possess pleiotropic and potent effector function
in acute and chronic inflammatory responses. The identity,
receptor specificity, and key effects of cytokines understood
to have particular importance in pathogenesis of human
autoimmunity and chronic inflammation are summarized in
Tables 23-1 through 23-8.

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CYTOKINES

Table 23-1 Interleukin-1 Superfamily Cytokines with Roles in Rheumatic Disease

Cytokine

Size (kD)*

Receptors

Major Cell Sources

Key Functions

IL-1

35 (pro)

IL-1RI

Monocytes; B cells; broblasts;

chondrocytes; keratinocytes

17 (active)

IL-1RAcP
IL-1RII (decoy)

Fibroblast cytokine, chemokine, MMP, iNOS, PG

release
Monocyte cytokine, ROI, PG
Osteoclast activation
Chondrocyte GAG synthesis ; iNOS, MMP, and
aggrecanase
Endothelial adhesion-molecule expression

35 (pro)

IL-1RI

Monocytes; B cells; PMNs;

epithelial cells; keratinocytes

Similar to IL-1

IL-1

17 (active)

IL-1RAcP

Autocrine growth factor (e.g., keratinocytes)

IL-1RII (decoy)
IL-1Ra

22

IL-1RI
IL-1RAcP
IL-1RII

Monocytes

Antagonize effects of IL-1 and IL-1

IL-33

30 (pro)

ST2L

Epithelial cells; monocytes; smooth

muscle cells; keratinocytes

Promote Th2 cell activation, mast cell activation,

and cytokine production

18 (active)

IL-1RAcP

23 (pro)

IL-18R

18 (active)

IL-18R

Monocytes; PMNs; dendritic cells;

platelets; endothelial cells

T cell effector polarization (Th1 with IL-12/Th2 with

IL-4)
Chondrocyte GAG synthesis ; iNOS expression
NK activation; cytokine release; cytotoxicity
Monocyte cytokine release; adhesion molecule
expression
PMN activation; cytokine release; migration
Endothelial cellsproangiogenic

IL-18

*Pro forms cleaved to active moieties by proteases, including caspase-1, calpain, elastase, and cathepsin G.
Pro-IL-1 retains bioactivity before cleavage.
GAG, glycosaminoglycan; iNOS, inducible nitric oxide synthase; MMP, matrix metalloproteinase; NK, natural killer; PG, peptidoglycan; PMN, polymorphonuclear
neutrophil; ROI, reactive oxygen intermediates.

Table 23-2 Tumor Necrosis Factor Superfamily Cytokines* with Potential Role in Rheumatic Disease
Cytokine Size (kD) Receptors

Major Cell Sources

Selected Functions

TNF-

Monocytes; T, B, NK cells; PMNs; eosinophils;

mast cells; broblasts; keratinocytes; glial
cells; osteoblasts; smooth muscle

Monocyte activation, cytokine, and PG

26 (pro)

TNF-RI (p55)
TNF-RII (p75)

LT

22-26

RANK
ligand

35

TNF-RI

T cells; monocytes; broblasts; astrocytes;

myeloma; endothelial cells; epithelial cells

Peripheral lymphoid development

Stromal cells; osteoblasts; T cells

Stimulates bone resorption via osteoclast maturation and

activation
Modulation of T cell-DC interaction

TNF-RII
RANK

PMN priming, apoptosis, oxidative burst

Endothelial cell adhesion molecule, cytokine release ;
broblast proliferation and collagen synthesis
MMP and cytokine
T cell apoptosis; clonal (auto)regulation; TCR dysfunction
Adipocyte FFA release
Endocrine effectsACTH, prolactin ; TSH, FSH, GH

Otherwise similar bioactivities to TNF-

OPG

55

RANKL

Stromal cells, osteoblasts

Soluble decoy receptor for RANKL

BLyS

18-32

TACI
BCMA
BLyS-R

Monocytes; T cells; DCs

B cell proliferation, Ig secretion, isotype switching, survival

T cell costimulation

APRIL

TACI
BCMA

Monocytes; T cells; tumor cells

B cell proliferation
Tumor proliferation

*Additional members of importance include TRAIL, TWEAK, CD70, FasL, and CD40L. At least 18 members of the family are now described.
Also called BAFF.
ACTH, adrenocorticotropic hormone; APRIL, a proliferation inducing ligand; BAFF, B cell activating factor belonging to the TNF family; BCMA, B cell maturation protein; BLyS, B lymphocyte stimulator protein; DC, dendritic cell; FFA, free fatty acid; GAG, glycosaminoglycan; LT, lymphotoxin; MMP, matrix metalloproteinase; NK, natural killer; OPG, osteoprotegerin; PG, peptidoglycan; PMN, polymorphonuclear neutrophil; RANK, receptor activator of NFB ligand; TACI,
transmembrane activator and calcium modulator and cyclophilin ligand; TNF, tumor necrosis factor; TRAIL, TNF related apoptosis-inducing ligand; TWEAK,
TNF-like weak inducer of apoptosis.

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Table 23-3 Cytokines Associated Predominantly with Effector Function for T Cells*
Cytokine

Size (kD)

Receptors

Major Cell Sources

Key Functions

20-25

IFNR

Th/c1 cells; NK cells; T cells;

B cells; macrophage/DCs

Macrophage activation, DC APC function

Th/c cells; NK cells

T cell division; maturation; cytokine release;

cytotoxicity
NK cell cytokine release; cyotoxicity; monocyte
activation
Lymphocyte apoptosis
Th2 differentiation, maturation, apoptosis
B cell maturation; isotype switch (IgE)
Eosinophil migration, apoptosis
Endothelial activation; adhesion molecule
expression
B cell differentiation; immunoglobulin
production (IgA)
Eosinophil differentiation and activation
Th/c maturation

Type II Interferon
IFN-

Endothelial adhesion molecule

MHC class II expression
T cell growth ; opposes Th2 responses
Bone resorption ; broblast collagen synthesis

4a-Helix Family
IL-2

15

IL-2R
IL-2/15R -chain

IL-4

20

IL-4R/-chain
IL-4R/IL-13R1

Th/c cells (Th2); NK cells

IL-5

25 monomer

IL-5R

50 homodimer

IL-5R

Th/c2 cells; NK cells; mast cells;

epithelial cells

IL-17A

20-30

IL-17R

T cells (Th17); broblasts

IL-25 (IL-17E)

20-30

IL-17R

Th2 cells

IL-17 Family
Chemokine release, broblast cytokine release,
MMP release
Osteoclastogenesis; hematopoiesis
Chondrocyte GAG synthesis
Leukocyte cytokine production
Th2 cytokine release; B cell IgA and IgE synthesis; eosinophilia; epithelial cell hyperplasia

*Additional T cellderived cytokines of potential interest include IL-13 from Th2 and NK2 cells.
IL-17 family also contains IL-17B, IL-17C, and IL-17F, the distinct functions of which are currently unclear.
APC, antigen presenting cell; DC, dendritic cell; GAG, glycosaminoglycan; IFN, interferon; MHC, major histocompatibility complex; MMP, matrix metalloproteinase; NK, natural killer; Th/c, T helper/cytotoxic.

CYTOKINES IN ACUTE INFLAMMATION

Cytokines operate at every stage in the crucial early events
that promote acute inflammation. Cells that make up the
innate immune response, including neutrophils, natural killer
cells, macrophages, mast cells, and eosinophils, all produce and
respond to cytokines generated within seconds of tissue insult.
Cytokines prime leukocytes for response to microbial and
chemical stimuli; upregulate adhesion molecule expression on
migrating leukocytes and endothelial cells; and amplify the
release of reactive oxygen intermediates, nitric oxide, vasoactive amines, and neuropeptides, and the activation of kinins and
arachidonic acid derivatives, prostaglandins, and leukotrienes,
which regulate cytokine release. Similarly, cytokines regulate the
expression of complement processing and membrane defense
molecules, scavenger receptors, NOD Like Receptor (NLR),
and Toll-like receptors. Cytokines, particularly IL-1, TNF-,
and IL-6, are crucial in driving the acute-phase response. Tables
23-1 through 23-8 provide descriptions of the function of cytokines expressed within the acute inflammatory response.

be considered fluid states in which individual cells under

cytokine control transiently contribute to organized functional subunitssuch as the ectopic germinal center, synovial lining layer, or renal interstitial nephritisyet remain
competent to migrate thereafter under the influence of
chemotactic gradients on the extracellular matrix. Cytokines also may promote cell death (apoptosis) either by
withdrawal (e.g., IL-2, IL-7, IL-15) or by binding cytokine
receptors containing death domains (e.g., TNF-R1). Cytokines contribute at every stage of inflammatory lesion development in a dynamic equilibrium, rather than in a static,
linear manner. Chronic inflammation in rheumatic disease
usually contains cytokine activities reminiscent of innate
and acquired immune responses. For convenience, cytokines
can be considered by their effect on cell subsets and cellular
interactions (Fig. 23-2 describes a notional positioning for
cytokine activity in a developing and chronic lesion). Investigation of cytokine-regulated pathways in several rheumatic
diseases has identified several common pathways.

CYTOKINES IN CHRONIC INFLAMMATION

T Cell Effector Function in Chronic Inammation

Cytokines critically modulate the cellular interactions that

characterize chronic inflammation. Studies using real-time
image analytic techniques, such as two-photon microscopy
and confocal scanning, suggest continuous cellular motility
during inflammation. Inflammatory lesions might properly

T cells depend on cytokine function at every developmental stage from bone marrow stem cell maturation,
through thymic education, to functional determination and maturation after primary or secondary antigen
exposure. The last-mentioned is of prime importance

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CYTOKINES

Table 23-4 Cytokines Described Initially with Primary Role in Regulation of T Cells*
Cytokine

Size

Receptors

Major Cell Sources

Key Functions

IL-12

IL-12/23p40
IL-12p35

IL-12R
IL-12R1
IL-12R2

Macrophages; DCs

Th1 cell proliferation, maturation

T cell cytotoxicity
B cell activation

IL-23

IL-12/23p40

IL-23R

Macrophages; DCs

IL-23p19

IL-12R1

Th17 cell expansion and activation; IL-17

release

IL-15

15 kD

IL-15R

Monocytes; broblast; mast

cells; B cells; PMNs; DCs

T cell chemokinesis, activation, memory

maintenance
NK cell maturation, activation, cytotoxicity
Macrophage activation, suppression (dose
dependent)
PMN activation, adhesion molecule, oxidative burst
Fibroblast activation
B cell differentiation and isotype switching

Activated T cells; others (?)

B cell activation

IL-2/15R -chain

IL-21

15 kD

IL-21R -chain

*Cytokines included in this table are now understood to exhibit considerable functional heterogeneity as shown. Other T cell regulatory cytokines have been
described, including IL-27, the functions of which are currently under investigation.
DC, dendritic cells; NK, natural killer; PMN, polymorphonuclear neutrophil.

Table 23-5 IL-10 Superfamily Cytokines*

Cytokine

Receptors

Cellular Sources

Key Functions

IL-10

IL-10R1

Monocytes; T cells; B cells; DCs;

epithelial cells; keratinocytes

Macrophage cytokine release, iNOS, ROI ; soluble

receptor
T cell cytokine release, MHC expression ; anergy
induction
Treg cell maturation; effector function (?)
DC activation, cytokine release
Fibroblast MMP, collagen release ; no effect on TIMP
B cell isotype switching enhanced

IL-10R2

IL-19

IL-20R1/IL-20R2

Monocytes; others (?)

Monocyte cytokine and ROI release; monocyte apoptosis

IL-20

IL-22R/IL-20R2
IL-20R1/IL-20R2

Keratinocytes; others (?)

Autocrine keratinocyte growth regulation

IL-22

IL-22R/IL-10R2

Th17 cells; CD8 T cells; T cells;

NK cells

Acute-phase response, keratinocyte activation proliferation

IL-24

IL-22R/IL-20R2
IL-20R1/IL-20R2

Monocytes; T cells

Tumor apoptosis; Th1 cytokine release by PBMC

*Additional members include IL-26, IL-28, and IL-28A. Many functions of IL-10 superfamily are as yet poorly understood, but they likely reside beyond the
immune system.
DC, dendritic cell; iNOS, inducible nitric oxide synthase; MMP, matrix metalloproteinase; NK, natural killer; PBMC, peripheral blood mononuclear cells;
ROI, reactive oxygen intermediates; TIMP, tissue inhibitor of metalloproteinase.

because re-education of phenotypic T cell responses may

be achieved through alteration of the ambient cytokine
milieu. T cell receptorpeptidemajor histocompatibility complex (MHC) interactions during T celldendritic
cell interaction rely on costimulatory molecule and local
cytokine expression to determine functional outcome
(see Tables 23-3 and 23-4). IL-12, in the presence of IL18, promotes type 1 phenotypic development, characterized ultimately by IFN- producing T helper type 1 (Th1)
effector cells.20 IFN- drives macrophage priming and
activation and adhesion molecule expression and promotes granuloma formation and microbial killing. IFN-
has a complex role in tissue destruction, however, with
contradictory data obtained in inflammation models in
IFN--deficient and IFN- receptordeficient mice. IFN-
ultimately may retard tissue destruction, perhaps by suppressing osteoclast activation.21

A novel T cell subset has been defined that secretes

IL-17A predominantly (Th17 effector cells), together
with IL-22. Th17 cells are generated in the presence of IL6 and transforming growth factor (TGF)-, expanded by
IL-1 and IL-23, and antagonized by IL-25 (IL-17E) and
paradoxically by IFN-. IL-17A provides a direct and rapid
route to tissue damage via such means as osteoclast activation or FLS activation.22 The precise contribution of Th17
cells in human autoimmune disease is currently unclear.
There are, however, persuasive data from rodent models
indicating that Th17 cells may be of primary importance as
initiator and effector cells. IL-4 dominance during T cell
dendritic cell interactions in the presence of IL-18 leads
to type 2 responses, which promote humoral immunity
driven by Th2 cells synthesizing primarily IL-4, IL-5, IL10, and IL-13. Resulting pathogenesis more likely may be
B cellmediated. Cytokines that predispose to regulatory

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373

Table 23-6 IL-6 Superfamily Cytokines*

Cytokine

Size (kD) Receptors

Major Cell Sources

Key Functions

Monocytes; broblasts; B cells; T cells

B cell proliferation; immunoglobulin production

Hematopoiesis, thrombopoiesis
T cell proliferation, differentiation, cytotoxicity
Hepatic acute-phase response
Hypothalamic-pituitary-adrenal axis
Variable effects on cytokine release by monocytes

IL-6

21-28

IL-6R

Oncostatin M

28

OMR gp130

Monocytes; activated T cells

Megakaryocyte differentiation
Fibroblast, TIMP, and cytokine release
Acute-phase reactants, broblast protease inhibitors
Monocyte TNF release ; IL-1 effector function
Hypothalamic-pituitary axis ; corticosteroid release
Modulatory effect on osteoblast (?)
Proinammatory effects in some models (?)

Leukemia
inhibitory
factor

58

LIFR gp130

Fibroblasts; monocytes; lymphocytes;

mesangial cells; smooth muscle cells;
epithelial cells; mast cells

Acute-phase reactants

gp130

Hematopoiesis, thrombopoiesis
Role in neural development, neural effector function,
implantation
Bone metabolism; extracellular matrix regulation
Leukocyte adhesion molecule expression
Eosinophil priming
Mixed proinammatory versus anti-inammatory
effects in models
*Additional members of potential importance include IL-11, cardiotropin-1, and ciliary neurotrophic factor. Note overlapping effects within family.
Membrane or soluble form can dimerize gp130 to promote signaling, which promotes signal transduction.
LIFR, leukemia inhibitory factor receptor; OMR, oncostatin M receptor; TIMP, tissue inhibitor of metalloproteinase; TNF, tuimor necrosis factor.

T cell development are unclear, although high levels of IL10 or TGF- have been suggested in this context.23 Effector
T cells can operate via secretion of cytokines to patterns
determined by their prior activatory conditions.
Cognate Cellular Interactions
In many inflammatory lesions, there is relative paucity
of inducer T cellderived cytokines (especially IFN-),
despite abundant proinflammatory cytokine expression.
Cell-cell membrane interactions between leukocyte subsets
and between tissue cells and leukocytes have emerged as
a dominant mechanism sustaining chronic inflammation.
Cytokines contribute to these interactions at several levels (Fig. 23-3), including directly as membrane-expressed
ligands, indirectly via activating cells, and synergistically by
enhancing their subsequent cognate activities. The importance of cytokine-cell contact interactions is best studied in
synovial tissues, but applies to many inflammatory lesions.
Many data now show that cognate interactions between T
cells and adjacent macrophages constitute a major pathway
driving cytokine release, and that cytokines sustain this
pathway (see Fig. 23-3). Such interactions do not depend
on T cell receptormediated T cell activation and provide a
route to expansion of inflammation by T cells, but independent of local autoantigen recognition.
Vey and colleagues24 first observed monocyte activation via cell contact with mitogen-stimulated T cells.
Freshly isolated synovial T cells activate macrophages by
this mechanism, confirming that contact-induced cellular activation is a fundamental property of inflammatory
T cells.25 Antigen-independent, cytokine-mediated bystander
activation confers this capacity on human CD4+ memory
T cells.26 Studies using synovial T cells from rheumatoid

arthritis and psoriatic arthritis tissues reveal that exposure of

memory T cells to synergistic combinations of cytokines are
most potent in this respect, particularly IL-15, TNF-, and
IL-6.27,28 Cytokine activities also operate directly on macrophages to synergize with T cell contact. IFN- and IL-18 are
most potent in this respect, acting via increased adhesion
molecule expression.
Activated memory CD4+ and CD8+ T cells promote cytokine release from macrophages via diverse membrane ligands,
including LFA-1/ICAM-1, CD69, and CD40/CD154.27,29 After
contact with T cells, macrophages release increased concentrations of TNF- and IL-1, but not IL-10, and they exhibit reduced
levels of IL-1Ra. Th1 cells promote relatively greater proinflammatory cytokine release than do Th2 cells after coculture. This
finding suggests that their functional phenotype extends beyond
cytokine secretion to include a differential membrane receptor
array.30 This suggestion is borne out further in the relative phenotypic distinctions between Th1 (CD40L, CCR5, IL-18R) and
Th2 (ST2, CXCR3) cells. The role of Th17 cells in this context is
unknown. Signaling pathways engaged in monocytes after such
T cellmembrane interactions are distinct from the pathways
activated by conventional cytokine-inducing agents. Distinct
use of phosphatidylinositol 3-kinase, NFB, and p38 mitogenactivated protein kinase pathways is observed.31 Similarly, discrete macrophage signals follow contact with cytokine-activated
T cells (which resemble synovial T cells) compared with T cell
receptoractivated T cells.32 Such distinctions offer therapeutic
potential in targeting cytokine-activated, T celldriven pathways, leaving antigen-driven responses relatively intact. The
activation state of memory T cells necessary for the previously
discussed interactions to proceed remains controversial. Purified
resting T cell subsets activate synovial fibroblasts to release IL-6,
IL-8, matrix metalloproteinase 3 (MMP3), and prostanoids, in
synergy with IL-17.33

374

MCINNES

CYTOKINES

Table 23-7 Growth Factors Relevant to Rheumatic Diseases

Cytokine

Receptors

Cellular Sources

Key Functions

TGF-*

Type I TGFR

Broadincluding broblasts,
monocytes, T cells, platelets

Wound repair, matrix maintenance, and brosis

Isoforms 1-3

Type II TGFR

Initial activation then suppression of inammatory

responses
T cell (Treg and Th17) and NK cell proliferation and
effector function
Early-phase leukocyte chemoattractant, gelatinase,
and integrin expression
Early macrophage activation then suppression,
reduced iNOS expression

Others

BMP family
(BMP2-15)

BMPRI

Varied (e.g., epithelial and

mesenchymal embryonic tissues);
bone-derived cell lineages

Regulate critical chemotaxis, mitosis, and differentiation processes during chondrogenesis and
osteogenesis, tissue morphogenesis (e.g., heart,
skin, eye)

Platelets; macrophages; endothelial

cells; broblasts; glial cells; astrocytes;
myoblasts; smooth muscle cells

Local paracrine or autocrine growth factor for variety of lineages

BMPRII
PDGF

PDGFR
PDGFR

FGF family

FGFR (various)

Wound healing
Widespread

Growth and differentiation of mesenchymal,

epithelial, and neuroectodermal cells

Basic FGF
Acidic FGF
*Members of TGF- superfamily include BMP, growth and differentiation factor, inhibinA, inhibinB, mllerian inhibitory substance, glial-derived neurotrophic
factor, and macrophage inhibitory cytokine.
Bound to latency-associated peptide to form small latency complex and to latent TGF- binding protein to form large latent complex; activated by
proteolytic and nonproteolytic pathways.
BMP, bone morphogenetic protein; FGF, broblast growth factor; iNOS, inducible nitric oxide synthase; NK, natural killer; PDGF, platelet-derived growth
factor; TGP, transforming growth factor.

It is likely that T cells may be activated by interactions with diverse moieties, including extracellular matrix
components and potentially autoantigens. Nevertheless,
it is now clear that cytokines can promote chronicity by
activating T cells to promote inflammation regardless of
local (auto)antigen recognition, and that this has enormous
therapeutic potential (see Fig. 23-3).
Agonist/Antagonist Cytokine Activities in Chronic
Inammation
Complex regulatory interactions exist to suppress ongoing
inflammatory responses. This is often achieved via parallel
secretion of antagonistic cytokines and soluble receptors to
regulate cytokine effector pathways. Th1 responses are suppressed partly by cytokines of Th2 type (e.g., IL-4 or IL-10),
and consequently exaggerated Th1 responses arise in models in which the Th2 response is deficient.20 Th1 and Th2
cells similarly limit Th17 cell expansion.22 Similar regulatory loops operate for other leukocytes, exemplified by the
yin-yang effects of TNF- and IL-10 on macrophage cytokine release and effector function.34
Inhibitory cytokine activities usually are defined with
respect to a proinflammatory cytokine, and in other contexts
they may have quite distinct function, rendering prediction
of their net contribution to an inflammatory response difficult. IL-10 opposes many of the proinflammatory effects of
TNF- and IL-1 (e.g., reduces adhesion molecule expression, MHC expression, and MMP release), but it potently
activates B cell activation and immunoglobulin secretion.34
Similarly, TNF-, which is normally considered a proinflammatory moiety, may have an important role in regulating

T cell function because T cells removed from sites of chronic

inflammation exhibit suppressed capacity to signal via their
T cell receptor that recovers on TNF- neutralization.35
Such regulation is complicated further by the precise ratio
of cytokine to soluble receptor, such as TNF to sTNFR or
IL-10 to sIL-10R, within the local environment. Commensurate with this, administration of anti-inflammatory cytokines, such as IL-4, IL-10, and IL-11, has generally proved
disappointing in the context of clinical inflammatory diseases. An important caveat is the potential requirement of
combinations of cytokines to suppress inflammation optimally (e.g., combinations including IL-4, IL-10, and IL-11).
Further functional antagonism is exemplified in the antagonistic activities of IL-1 and IL-1Ra and of IL-18 and IL-18
binding protein in regulating macrophage activation.
The role of cytokines in regulating cognate interactions between leukocytes also has emerged more recently.
Although anti-inflammatory pathways are poorly induced
after cell contact, cytokine-activated T cells can induce
IL-10 release by monocytes.32 Rheumatoid arthritis synovial
membrane IL-10 release, which is partially T cell dependent, feeds back to regulate TNF- release. Cytokine production from adjacent cell lineages within an inflammatory
lesion also may be suppressive. IFN- reduces mitogenactivated, T cellinduced macrophage release of TNF and IL-1, whereas IL-1Ra release is enhanced.36 This
provides a mechanism whereby type I IFNs could modify
proinflammatory cytokine production. Regulation extends
beyond conventional cytokine activities. Prostaglandins
and lipoprotein moieties, particularly high-density lipoprotein, can suppress cytokine-mediated, T cellmacrophage
interactions.37

PART 3

EFFECTOR MECHANISMS IN AUTOIMMUNITY AND INFLAMMATION

375

Table 23-8 Miscellaneous Cytokines with Potential Roles in Rheumatic Diseases

Cytokine

Size (kD)

Receptors

Cellular Sources

Key Functions

MIF

12

Unclear

Macrophages; activated T cells;

broblasts (synoviocytes)

Macrophage cytokine release, phagocytosis, NO release

T cell activation; DTH
Fibroblast proliferation; COX expression;
PLA2 expression
Intrinsic oxidoreductase activity
(cytozyme)

HMGB1

30

RAGE, dsDNA

Widespread expression; necrotic cells;

macrophages; pituicytes

DNA-binding transcription factor

Others (?)

GM-CSF

14-35

GM-CSFR

Necrosis-induced inammation
Macrophage activationdelayed proinammatory cytokine
Smooth muscle chemotaxis
Disrupts epithelial barrier function
Bactericidal (direct)
T cells; macrophages; endothelial cells;
broblasts

Granulocyte and monocyte maturation;

hemopoietic effects
Leukocyte PG release; DC maturation
Pulmonary surfactant turnover

G-CSFR

Monocytes; PMNs; endothelial cells;

broblasts; various tumor cells;
stromal cells

Granulocyte maturation; promotes PMN

function

GM-CSFR
G-CSF

19

M-CSF

28-44

M-CSFR

Monocytes; broblasts; endothelial cells

Monocyte activation, maturation

IL-32-

Unknown

Unknown

Monocytes; T cells; NK cells; epithelial cells

Promotes proinammatory cytokine

release from variety of cells

Type I
interferons
IFN/
family

Various

IFNR

Widespread

Antiviral response

Broad immunomodulatory effects (promotes MHC expression)

Macrophage activation; lymphocyte
activation and survival
Antiproliferative, cytoskeletal alteration,
differentiation
COX, Cyclooxygenase; DC, dendritic cell; DTH, delayed-type hypersensitivity; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage
colony-stimulating factor; HMGB, high mobility group box chromosomal protein; IFN, interferon; M-CSF, macrophage colony-stimulating factor; MIF, macrophage inhibitory factor; NO, nitric oxide; PG, prostaglandin; PLA, phospholipase A; PMN, polymorphonuclear neutrophil; RAGE, receptor for advanced glycation
end products.

Disease-Modifying Antirheumatic Drugs

Conventional disease-modifying antirheumatic drugs also can
act via modulation of cytokine production. Methotrexate modulates release of various cytokines in vitro, in part mediated via
adenosinecyclic adenosine monophosphate pathway.38 The
active metabolite of the dihydroorotate dehydrogenase inhibitor leflunomide, A77 11726, reduces TNF-, IL-1, IL-6, and
MMP-1, but it does not reduce IL-1Ra release by monocytes
after mitogen-activated T cell contact.39,40 Leflunomide may
mediate these activities through modulation of inhibitor of
NFB (IB) phosphorylation and degradation and AP-1
and c-Jun N-terminal protein kinase activation.41 Finally, sulfasalazine is an inhibitor of proinflammatory cytokine-induced
NFB. Biologic agents also potently modify cytokine expression in a variety of disease states.
Cellular Interactions across Diverse Tissues
Cytokines promote cognate cellular interactions across
a range of tissues. In contrast to T cellmacrophage and
T celldendritic cell interactions, in which adhesion molecule

and costimulatory pathways are often implicated, cell-cell

membrane communications apart from leukocyte-leukocyte
interactions are often mediated through membrane cytokine
expression (see Fig. 23-3). T cell contactmediated activation of fibroblasts operates via membrane TNF- and IFN-
to enhance fibroblast cytokine release and MMPbut not
tissue inhibitors of metalloproteinaseexpression, favoring
tissue destruction.29 The source and activation status of the
fibroblast are vital; fibroblast-like synoviocytes, but not cutaneous fibroblasts, are potently activated by this route. Other
studies have shown T cell contactmediated activation of
neutrophils, keratinocytes, mesangial cells (via a combination of membrane cytokine and CD40L expression), platelets, and renal tubule epithelial cells. Cytokine-activated
macrophages (via IFN- and sCD40L) may interact via
cell contact with mesangial cells to activate adhesion molecule and chemokine release by the latter. Cell-cell contact between cells of the immune system and beyond likely
represents a ubiquitous mechanism whereby perpetuation
of chronic inflammation is potently influenced by local
production of cytokines.

376

MCINNES

CYTOKINES

Fibroblast

DC
IL-17
IL-22

?
IL-12, IL-23
Chemokines, ECM
Co-stimulation

TNF-
LT
IL-1
IL-15
IL-18
IL-6
IL-20
IL-32
IL-33
RANKL
GM-CSF

T1/T17

IL-17, IL-22
IFN-
Cell contact, costimulation

Macrophage
TLR
NLR
Peptidoglycan
Lipopolysaccharide
Heat shock proteins

Neutrophil

Mast cell

Tissue cell

IL-10
IL-1Ra
IL-18BP
sIL-1R
sTNFR
IL-27
IL-35
TGF-

Endothelial cell

C
H
R
O
N
I
C
I
N
F
L
A
M
M
A
T
I
O
N

FcR
Immune complexes
Acute phase reactants
Complement

B cell

BLyS
APRIL

Figure 23-3 Cytokines regulate complex cellular networks in chronic inammation. Cytokines regulate interactions between T1 cells and antigen
presenting cells (dendritic cells [DC]), and thereafter they promote cell-cell contact and soluble interactions between T cells, macrophages, neutrophils,
endothelial cells, broblasts, B cells, and target tissue cells (e.g., mesangial cells, renal tubular epithelial cells, keratinocytes). Tissue cells may make
substantial contributions to organ dysfunction through inammatory mediator release. Crucial to these pathways are the synergistic combinations of
cytokines that operate as cassettes (synergistic teams) or together with cell-cell, contact-dependent interactions. The latter are mediated via membrane cytokine expression or through cell surface receptors, including integrin and immunoglobulin superfamily adhesion molecules and members of
the interleukin (IL)-1R and tumor necrosis factor (TNF)receptor superfamilies. Chronicity is maintained on the basis of overproduction of proinammatory moieties relative to the presence of anti-inammatory mediators. Soluble cytokines also regulate activation of additional effector leukocytes
(see Tables 23-1 through 23-8), including mast cells and eosinophils, which are not shown here because they may not be characteristic of the T helper
type 1 (Th1) response shown. They may be relevant, however, in inammatory arthritis. ECM, extracellular matrix; FcR, Fc receptor; IFN, interferon; TGF,
transforming growth factor; TLR, Toll-like receptor.

B Cells and Cytokine Release in Chronic Inammation

Growth Factors in Chronic Inammation

Cytokines are crucial to B cell maturation, proliferation,

activation, isotype switching, and survival (see Chapter 10).
Cytokine-mediated B cell activation is important in immune
complex generation, B cell antigen presentation, B cellT
cell interactions, and germinal center formation. Particular
importance has been placed on the TNF superfamily cytokines, BLyS and APRIL. These cytokines are crucial for B
cell development, survival, and optimal activation. B cells
represent a potent source of cytokines such as IL-6 and IL-10.
B cells also have been considered important inducers of macrophage-derived cytokine release. This process may operate
primarily via immune complex formation42 or through regulation of T cell activation (with B cell help). Complex regulatory feedback loops involving cytokine expression and B cells
are likely important in a range of rheumatic diseases in which
B cells are of paramount pathophysiologic importance.

Many data document the importance of growth factor families in chronic inflammation. TGF- superfamily members,
including TGF- isoforms and bone morphogenetic protein family members, warrant particular reference. TGF-
is critically involved in processes of cell proliferation, differentiation, inflammation, and wound healing.43 Bone morphogenetic proteins, in addition to regulating inflammatory
responses, are paramount in determining cartilage and bone
tissue development and remodeling.44 As such, they are of
increasing interest in the pathogenesis of several rheumatic
diseases.

Innate Cell Lineages in Chronic Inammation

Cytokines potently activate innate response cells that
contribute to the chronic inflammatory lesion of a variety
of rheumatic diseases. Tables 23-1 through 23-8 document
relevant examples in which neutrophils, natural killer cells,
eosinophils, and mast cells may be recruited and activated
by the presence of appropriate cytokine combinations.

CYTOKINE EFFECTS BEYOND IMMUNE

REGULATION
A striking feature of the cytokine field concerns the broad
functional pleiotropy exemplified in the effects of cytokines in normal physiologic and adaptive processes. Cytokine activities are found in muscle, adipose tissue, central
nervous system, and liver, mediating normal regulation of
metabolic pathways and modulation imposed by altered tissue conditions. Examples are found not only in the release
of adipokines that regulate adipose metabolic pathways, but
also in the release of conventional cytokines by fat pads in
inflammatory synovitis.

PART 3

SUMMARY
Cytokines represent a diverse family of glycoproteins active
across a broad range of tissues. Their pleiotropic functions
and propensity for synergistic interactions and functional
redundancy render them intriguing therapeutic targets. So
far, single cytokine targeting has proved useful in several
rheumatic disease states. Further elucidation of the biology
and functional interactions within this expanding family of
bioactive moieties is likely to prove informative in resolving
pathogenesis and in generating novel therapeutic options.
REFERENCES
1. Locksley RM, Killeen N, Lenardo MJ: The TNF and TNF receptor superfamilies: Integrating mammalian biology. Cell 104:487,
2001.
2. Marshak-Rothstein A: Toll-like receptors in systemic autoimmune
disease. Nat Rev Immunol 6:823, 2006.
3. Bresnihan B, Baeten D, Firestein GS, et al: OMERACT 7 Special
Interest Group: Synovial tissue analysis in clinical trials. J Rheumatol
32:2481, 2005.
4. Haringman JJ, Gerlag DM, Zwinderman AH, et al: Synovial tissue
macrophages: A sensitive biomarker for response to treatment in
patients with rheumatoid arthritis. Ann Rheum Dis 64:834, 2005.
5. Gadina M, Hilton D, Johnston JA, et al: Signaling by type I and II
cytokine receptors: Ten years after. Curr Opin Immunol 13:363,
2001.
6. Bravo J, Heath JK: Receptor recognition by gp130 cytokines.
EMBO J 19:2399, 2000.
7. Dubois S, Mariner J, Waldmann TA, et al: IL-15Ralpha recycles and
presents IL-15 in trans to neighboring cells. Immunity 17:537, 2002.
8. Francis K, Palsson BO: Effective intercellular communication distances are determined by the relative time constants for cyto/chemokine secretion and diffusion. Proc Natl Acad Sci U S A 94:12258,
1997.
9. Feldmann M, Andreakos E, Smith C, et al: Is NF-kappaB a useful therapeutic target in rheumatoid arthritis? Ann Rheum Dis 61(Suppl 2):13,
2002.
10. Hajeer AH, Hutchinson IV: TNF-alpha gene polymorphism: Clinical
and biological implications. Microsc Res Tech 50:216, 2000.
11. Hurme M, Lahdenpohja N, Santtila S: Gene polymorphisms of interleukins 1 and 10 in infectious and autoimmune diseases. Ann Med
30:469, 1998.
12. Kontoyiannis D, Pasparakis M, Pizarro TT, et al: Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements:
Implications for joint and gut-associated immunopathologies. Immunity 10:387, 1999.
13. Anderson P: Post-transcriptional regulation of tumour necrosis factor
alpha production. Ann Rheum Dis 59:3, 2000.
14. Gueydan C, Droogmans L, Chalon P, et al: Identification of TIAR as
a protein binding to the translational regulatory AU-rich element of
tumor necrosis factor alpha mRNA. J Biol Chem 274:2322, 1999.
15. Saito K, Chen S, Piecyk M, et al: TIA-1 regulates the production of
tumor necrosis factor in macrophages, but not in lymphocytes. Arthritis Rheum 44:2879, 2001.
16. Budagian V, Bulanova E, Paus R, et al: IL-15/IL-15 receptor biology: A
guided tour through an expanding universe. Cytokine Growth Factor
Rev 17:259, 2006.
17. Ferrari D, Chiozzi P, Falzoni S, et al: Extracellular ATP triggers IL-1
beta release by activating the purinergic P2Z receptor of human macrophages. J Immunol 159:1451, 1997.
18. Fantuzzi G, Dinarello CA: Interleukin-18 and interleukin-1 beta: Two
cytokine substrates for ICE (caspase-1). J Clin Immunol 19:1, 1999.
19. Wallach D, Varfolomeev EE, Malinin NL, et al: Tumor necrosis
factor receptor and Fas signaling mechanisms. Annu Rev Immunol
17:331, 1999.
20. Liew FY: T(H)1 and T(H)2 cells: A historical perspective. Nat Rev
Immunol 2:55, 2002.
21. Takayanagi H, Kim S, Taniguchi T: Signaling crosstalk between
RANKL and interferons in osteoclast differentiation. Arthritis Res
4(Suppl 3):S227, 2002.

EFFECTOR MECHANISMS IN AUTOIMMUNITY AND INFLAMMATION

377

22. Weaver CT, Harrington LE, Mangan PR, et al: Th17: An effector
CD4 T cell lineage with regulatory T cell ties. Immunity 24:677,
2006.
23. Shevach EM, DiPaolo RA, Andersson J, et al: The lifestyle of naturally occurring CD4+ CD25+ Foxp3+ regulatory T cells. Immunol
Rev 212:60, 2006.
24. Vey E, Zhang JH, Dayer JM: IFN-gamma and 1,25(OH)2D3 induce
on THP-1 cells distinct patterns of cell surface antigen expression,
cytokine production, and responsiveness to contact with activated
T cells. J Immunol 149:2040, 1992.
25. McInnes IB, Leung BP, Sturrock RD, et al: Interleukin-15 mediates T cell-dependent regulation of tumor necrosis factor-alpha
production in rheumatoid arthritis. Nat Med 3:189, 1997.
26. Unutmaz D, Pileri P, Abrignani S: Antigen-independent activation
of naive and memory resting T cells by a cytokine combination. J Exp
Med 180:1159, 1994.
27. McInnes IB, Leung BP, Liew FY: Cell-cell interactions in synovitis:
Interactions between T lymphocytes and synovial cells. Arthritis Res
2:374, 2000.
28. Sebbag M, Parry SL, Brennan FM, et al: Cytokine stimulation of
T lymphocytes regulates their capacity to induce monocyte production of tumor necrosis factor-alpha, but not interleukin-10: Possible
relevance to pathophysiology of rheumatoid arthritis. Eur J Immunol
27:624, 1997.
29. Dayer JM, Burger D: Cytokines and direct cell contact in synovitis:
Relevance to therapeutic intervention. Arthritis Res 1:17, 1999.
30. Ribbens C, Dayer JM, Chizzolini C: CD40-CD40 ligand (CD154)
engagement is required but may not be sufficient for human T helper
1 cell induction of interleukin-2- or interleukin-15-driven, contactdependent, interleukin-1beta production by monocytes. Immunology
99:279, 2000.
31. Hayes AL, Smith C, Foxwell BM, et al: CD45-induced tumor necrosis factor alpha production in monocytes is phosphatidylinositol
3-kinase-dependent and nuclear factor-kappaB-independent. J Biol
Chem 274:33455, 1999.
32. Foey A, Green P, Foxwell B, et al: Cytokine-stimulated T cells induce
macrophage IL-10 production dependent on phosphatidylinositol
3-kinase and p70S6K: Implications for rheumatoid arthritis. Arthritis
Res 4:64, 2002.
33. Yamamura Y, Gupta R, Morita Y, et al: Effector function of resting
T cells: Activation of synovial fibroblasts. J Immunol 166:2270, 2001.
34. Fickenscher H, Hor S, Kupers H, et al: The interleukin-10 family of
cytokines. Trends Immunol 23:89, 2002.
35. Cope AP: Studies of T-cell activation in chronic inflammation.
Arthritis Res 4(Suppl 3):S197, 2002.
36. Jungo F, Dayer JM, Modoux C, et al: IFN-beta inhibits the ability of
T lymphocytes to induce TNF-alpha and IL-1beta production in
monocytes upon direct cell-cell contact. Cytokine 14:272, 2001.
37. Hyka N, Dayer JM, Modoux C, et al: Apolipoprotein A-I inhibits
the production of interleukin-1beta and tumor necrosis factor-alpha
by blocking contact-mediated activation of monocytes by T lymphocytes. Blood 97:2381, 2001.
38. Chan ES, Cronstein BN: Molecular action of methotrexate in inflammatory diseases. Arthritis Res 4:266, 2002.
39. Breedveld FC, Dayer JM: Leflunomide: Mode of action in the treatment of rheumatoid arthritis. Ann Rheum Dis 59:841, 2000.
40. Burger D, Begue-Pastor N, Benavent S, et al: The active metabolite of
leflunomide, A77 1726, inhibits the production of prostaglandin E(2),
matrix metalloproteinase 1 and interleukin 6 in human fibroblast-like
synoviocytes. Rheumatology (Oxf) 42:89, 2003.
41. Manna SK, Mukhopadhyay A, Aggarwal BB: Leflunomide suppresses
TNF-induced cellular responses: Effects on NF-kappa B, activator
protein-1, c-Jun N-terminal protein kinase, and apoptosis. J Immunol
165:5962, 2000.
42. Chantry D, Winearls CG, Maini RN, et al: Mechanism of immune
complex-mediated damage: Induction of interleukin 1 by immune
complexes and synergy with interferon-gamma and tumor necrosis
factor-alpha. Eur J Immunol 19:189, 1989.
43. Chen W, Wahl SM: TGF-beta: Receptors, signaling pathways and
autoimmunity. Curr Dir Autoimmun 5:62, 2002.
44. Abe E: Function of BMPs and BMP antagonists in adult bone. Ann N
Y Acad Sci 1068:41, 2006.