Cellular Signalling 24 (2012) 11851194

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Cellular Signalling
journal homepage: www.elsevier.com/locate/cellsig

Review

The macrophage response towards LPS and its control through the
p38 MAPKSTAT3 axis
Johannes G. Bode , 1, Christian Ehlting 1, Dieter Hussinger
Department of Gastroenterology, Hepatology and Infectious Disease, University Hospital, Heinrich Heine University of Dsseldorf, Moorenstrasse 5, 40225 Dsseldorf, Germany

a r t i c l e

i n f o

Article history:
Received 8 January 2012
Accepted 27 January 2012
Available online 4 February 2012
Keywords:
TLR-signaling
Signal-transduction
Macrophages
Inammation
Endotoxin
Anti-inammatory signaling

a b s t r a c t
In macrophages detection of gram-negative bacteria particularly involves binding of the outer-wall component lipopolysaccharide (LPS) to its cognate receptor complex, comprising Toll like receptor 4 (TLR4),
CD14 and MD2. LPS-induced formation of the LPS receptor complex elicits a signaling network, including
intra-cellular signal-transduction directly activated by the TLR4 receptor complex as well as successional induction of indirect autocrine and paracrine signaling events. All these different pathways are integrated into
the macrophage response towards an inammatory stimulus by a highly complex cross-talk of the pathways
engaged. This also includes a tight control by several intra- and inter-cellular feedback loops warranting an
inammatory response sufcient to battle invading pathogens and to avoid non-essential tissue damage
caused by an overwhelming inammatory response. Several evidences indicate that the reciprocal crosstalk between the p38MAPKpathway and signal transducer and activator of transcription (STAT)3-mediated
signal-transduction forms a critical axis successively activated by LPS. The balanced activation of this axis is
essential for both induction and propagation of the inammatory macrophage response as well as for the
control of the resolution phase, which is largely driven by IL-10 and sustained STAT3 activation. In this context regulation of suppressor of cytokine signaling (SOCS)3 expression and the recently described divergent
regulatory roles of the two p38 MAPK-activated protein kinases MK2 and MK3 for the regulation of LPSinduced NF-B- and IRF3-mediated signal-transduction and gene expression, which includes the regulation
of IFN, IL-10 and DUSP1, appears to play an important role.
2012 Elsevier Inc. All rights reserved.

Contents
1.
2.
3.
4.
5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
TLR4-induced signal-transduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Role of p38MAPK/MK2-transduced signal-transduction for TLR4-mediated activation . . . . . . . . . . . . . . . . . . . . . . . . . .
Regulation of cytokine secretion by LPS in macrophages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Regulation of the inammatory macrophage response through the cross-talk between STAT3- and p38 MAPK-mediated signal-transduction .
5.1.
STAT3 is the key effector molecule of IL-10 action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.
In macrophages SOCS3 prevents other STAT3-activating cytokines from mediating IL-10-like anti-inammatory effects . . . . . .
5.3.
The p38 MAPK pathway owns a key position in regulation of the inammatory response by orchestrating pro-inammatory as well as
anti-inammatory effector mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.
Conclusions and outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction
In general mammalian cells recognize the presence of pathogens
through a group of receptor complexes, also termed as pattern
Corresponding author.
E-mail address: Johannes.Bode@med.uni-duesseldorf.de (J.G. Bode).
1
Authors contributed equally.
0898-6568/$ see front matter 2012 Elsevier Inc. All rights reserved.
doi:10.1016/j.cellsig.2012.01.018

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recognition receptors (PRR) specialized to detect conserved molecular structures that are essential to the life cycle of a pathogen. These
pathogen-borne molecular structures are also termed as pathogen associated molecular patterns (PAMP). Thereby, the term PRR encompasses a heterogeneous group of soluble, membrane-bound or
cytoplasmic receptor structures involved in the detection of PAMPs.
These molecular sensors are crucial to the initiation of innate immunity, constituting the rst line defense against microorganisms.

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Apart from initializing rather unspecic but immediately effective

measures of the host against invading pathogens, innate immunity
also plays a primordial role in the activation and formation of adaptive immunity. Notably, the pattern of activated PRRs and the processing of their inter- and intra-cellular signal-transduction largely
determine the response triggered by the respective PAMP. This already warrants that even the innate immune response of the host occurs reasonably PAMP adapted.
Although initially not recognized as a part of the pathogen recognition molecule system, C-reactive protein (CRP), a member of the
evolutionary highly conserved pentraxins family of proteins, originally described as a serum constituent of patients suffering from pneumococcal pneumonia reacting with the pneumococcal C
polysaccharide [1], was probably the rst PRR identied. Apart from
being a helpful clinical surrogate parameter for inammation, this
protein has been meanwhile recognized as a protein that binds and
opsonizes microbes, thereby activating the complement cascade.
CRP belongs to a heterogeneous group of pathogen recognition molecules that may be roughly summarized as humoral or soluble PRRs,
including the family of pentraxins, the lipid transferases and
peptidoglycan-recognition proteins [2,3]. These proteins are mainly
produced in hepatocytes in response to inammatory cytokines
such as TNF, IL-1 or IL-6 released during an inammatory response. Contrariwise, the toll like receptor (TLR) family of proteins
is membrane bound PRRs expressed by a variety of different cell
types either located at the cellular surface (TLR1, 2, 4, 5, 6 and 10)
or in the endosome (TLR3, 7, 8 and 9). The TLR family of proteins is
the best characterized family of PRRs with 10 and 12 functional
TLRs identied in human and mouse, respectively, which are involved
in the recognition of a variety of different extracellular and intracellular pathogen or damage associated molecular patterns [46].
Another group of membrane-bound PRRs, also termed as phagocytic PRRs, is mainly expressed on the surface of macrophages, neutrophils and dendritic cells and includes scavenger receptors,
macrophage mannose receptors and -glucan receptors [7,8]. These
proteins directly bind to pathogens, mediating their phagocytosis
into lysosomal compartments and subsequent elimination. Last but
not least the RNA helicase family of the RIG (retinoicacid-inducible
gene)-I like receptors (RLR) and the group of NOD like receptors
(NLR) represent cytoplasmic sensors able to recognize viral (RLR) or
bacterial intra-cellular PAMPs (NLR) [5,9]. RLR are also involved in
the detection of cytoplasmic DNA, such as e.g. bacterial DNA, if polymerase III dependently converted into double stranded RNA
(dsRNA). Apart from this, cytoplasmic DNA is also recognized by
other receptor systems including DNA dependent activator of interferon response factor (DAI) [10], absent in melanoma 2 (AIM2) [11]
and the protein termed stimulator of interferon genes (STING) [12].
The pattern and the intensity by which the different PRRs are
expressed by the different cell types of the mammalian organism
vary strongly and largely depend on cell function and localization.
However, in particular with respect to cell types that are not part of
the immune system in its most narrow sense, knowledge on the spectrum of PRR pattern expressed is fragmentary. This in particular, since
most expression analysis has been performed on the level of transcript while data on protein expression and functionality are incomplete and with respect to their in vivo relevance largely not
resolved. This may also result in an over-assessment of the relevance
of PRR expression in a variety of different cell types. Thus, for example
hepatocytes express transcripts for almost all TLRs [13] but their responsiveness to ligands such as lipopolysaccharide (LPS), one of the
most immune-stimulatory glycolipids constituting the outer membrane of the Gram-negative bacteria, in vivo is almost negligible
[14,15]. Consistently, upon macrophage depletion, hepatocytes do
not show nuclear translocation of NF-B in vivo upon treatment
with LPS [14], while it still occurs in hepatic stellate cells. Hence, in
the liver, hepatic stellate cells and macrophages are direct targets of

TLR4 ligands while the involvement of hepatocytes into the response

of an organism towards LPS occurs indirect and is mainly mediated
via macrophage-derived mediators [3,14]. This makes clear that the
mere detectability of TLRs within a respective cell type does not
allow to draw any conclusions with respect to the in vivo relevance
of this observation.
Stimulation of macrophages with LPS elicits a variety of different
signaling events that culminate in the activation of macrophage effector functions, including the production of cytokines, chemokines and
other communication signals important for the coordination of the
inammatory response. In the past it became increasingly evident
that this macrophage response is the result of a complex intracellular signaling network that integrates signals, which are directly
elicited by the activated TLR4 receptor complex and signals that are
parts of autocrine feedback loops. These processes have to be tightly
controlled as they not only orchestrate the inammatory response,
but also avert the detrimental effects of overwhelming macrophage
activation. In this context, in macrophages, the release of IL-10 and
subsequent induction of sustained activation of signal-transducer
and activator of transcription (STAT)3 (Fig. 1) are one of the most
critical anti-inammatory feedback mechanisms, as is discussed
below [1620]. Thereby, the LPS-induced release of IL-10 from macrophages is the result of a signaling network that includes autocrine
or paracrine feedback mechanisms [21]. Recent work suggested that
in this context the p38 MAPKpathway plays a key role for the orchestration of both, the initial inammatory cytokine response of the activated macrophage and its IL-10-mediated resolution. The present
review summarizes the signal-transduction and inammatory cytokine response elicited through the activation of TLR4 in macrophages
with a special focus on the crosstalk between the p38 MAPKpathway
and STAT3-mediated signals and its regulatory relevance for the inammatory macrophage response towards LPS. The TLR signaling in
general as well as the multifarious functions of p38 MAPK in cellular
signaling has been recently addressed in several comprehensive reviews [46,22,23] and will not be within the focus of this review.
2. TLR4-induced signal-transduction
The discovery of the Toll gene as an important component for the
detection of microbes in Drosophila melanogaster as well as the nding that Toll-like receptor (TLR)4 mediates the inammatory response to LPS in mice [2426] led to the identication of the target
molecule of LPS on the cellular surface of macrophages. These discoveries, for which Bruce Beutler and Jules Hoffman have been awarded
with the Noble Price for Medicine in 2011, substantially extended the
knowledge on pathogen-mediated intra-cellular signal transduction,
and were most crucial for understanding the mechanisms that govern
innate immunity. Thereby LPS itself poorly activates innate immunity
but requires LPS binding protein, forming a high-afnity complex
with the lipid A moiety of LPS, for transfer on CD14. This enables
LPS to be transferred to the LPS receptor complex composed of TLR4
and MD2. TLR4 is a type I transmembrane receptor protein comprising a conserved cytosolic region, termed the Toll-IL-1R (TIR) domain,
being characteristic for the IL-1 receptor/TLR superfamily and belongs
to a subgroup that is, like all the other TLRs, further characterized by a
large leucine rich repeat within its extracellular domain [27,28]. MD2
is associated with the extracellular domain of TLR4 and is essentially
required for cell surface expression of and LPS recognition by TLR4 as
well as for ligand-induced receptor clustering [2931]. The interaction between LPS and the TLR4/MD2 receptor complex triggers an
oligomerization of TLR4 and subsequent activation of signaling via
the cytoplasmic TIR domain of TLR4. Studies in CD11b/CD18-decient
macrophages further suggest that for expression of a full repertoire of
LPS-inducible genes CD14, TLR4, CD11b and CD18 must be coordinately engaged to deliver optimal intra-cellular signaling to the macrophage [32].

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Fig. 1. Relevance of the cross-talk between the p38MAPK pathway and STAT3-mediated signaling for the regulation of the inammatory macrophage response and its resolution.
A) Schematic summary of the cross-talk between the p38MAPK pathway and STAT3-dependent cytokine signaling in macrophages. LPS-binding to its receptor complex elicits
intra-cellular signal-transduction that results in changes of gene expression and in enhanced production of inammatory cytokines including cytokines such as IFN, IFN, IL-1, IL-6,
IL-12 and TNF. The production of these cytokines essentially requires activation of the p38MAPK pathway and results in a succession of autocrine/paracrine feed-back loops which in
turn modies LPS-induced cytokine expression. Hence the release of IFN interferon alpha receptor (IFNAR)1 dependently induces expression of IL-10 which in turn leads to a sustained
activation of STAT3 which in contrast to STAT3 activation induced by other cytokines such as IL-6 or IFN is insensitive to the endogenous inhibitor of STAT3-mediated cytokine signaling
suppressor of cytokine signaling (SOCS)3. Apart from STAT3 induction of SOCS3 also requires the activation of the p38MAPK pathway, which in turn is negatively regulated by the dual
specic phosphatase (DUSP)1. B) To show the effect of LPS on IFN-, IL-6- or IL-10-induced activation of STAT3 bone marrow derived macrophages were prepared as described [56]
and pre-treated with 100 ng/ml LPS as indicated. After the respective incubation period macrophages were stimulated with IFN (200 ng/ml), IL-6 (20 ng/ml) or IL-10 (20 ng/ml) for
another 20 min as depicted. Thereafter total protein extracts were prepared as described and subjected to immune-blot analysis [56] using antibodies specic for tyrosine phosphorylated
(PTyr STAT3) STAT3 or for threonine/tyrosine phosphorylated or total p38MAPK or SOCS3. GAPDH was detected for loading control. C) Demonstrates the timely succession of IFN and IL-10
production in BMDM macrophages treated with 100 ng/ml LPS. After the time periods indicated supernatant was analyzed by ELISA for the abundance of IFN and IL-10. For sake of clarity
the dynamics of protein concentration are depicted as percent from respective control conditions, which were set to 100% (basal levels for IFN were 17.3 +/ 12.8 pg/ml/10 6
cells and for IL-10 were 64.7 +/ 40.9 pg/ml/106 cells).

Downstream signaling of the TLR4 receptor complex in response

to LPS (summarized in Fig. 2A) is largely mediated via the recruitment of adapter proteins, including myeloid differentiation factor 88
(MyD88), MyD88 adapter-like protein (MAL), TIR-containing adapter
molecule (TRIF, also known as TICAM-1), and TRIF-related adapter
molecule (TRAM). Thereby, MAL-dependent recruitment of MyD88
orchestrates production of inammatory cytokines in response to
LPS-treatment [33,34]. This requires caspase 1 dependent processing
of MAL [35] and involves the activation of the IB/NFB pathway as
well as of the p38 MAPK and the c-jun N terminal kinase (JNK) members of the mitogen activated protein kinase (MAPK) family. In addition to the early MyD88-dependent signals TLR4 triggers a delayed
MyD88-independent [36], TRIF-dependent signal transduction [37]
via TRAF family member associated NF-B-activator binding kinase
(TBK)1-mediated activation of the IFN response factor (IRF)3 and
late activation of NF-B. This delayed part of TLR4 signaling requires
dynamin-dependent internalization of TLR4 and subsequent recruitment of TRAM which initiates TRIF-dependent pathways enabling
TLR4 to trigger the release of type I interferons [38]. The complexity

of TLR4 signaling is further increased by the fact that the inammatory response towards LPS is inuenced by the activity of the ATPbinding cassette transporters ABCA1 and ABCG1 linking TLR4 signaling towards regulation of the intra-cellular cholesterol ux and lipid
raft formation a point which has been comprehensively addressed
in a recent reviews [39].
3. Role of p38 MAPK/MK2-transduced signal-transduction for
TLR4-mediated activation
Both the MAL/MyD88 and the TRAM/TRIF-mediated signaling
pathways activate members of the MAP-kinase family. Thereby, subsequent to TLR4 activation MAL/MyD88 is thought to mediate early
activation of the MAPK family members p38 MAPK, ERK1/2 and JNK,
while late activation of these kinases is TRAM/TRIF-dependent
[40,41]. Activation of Erk1/2 further involves activation of Tpl2,
which has been demonstrated to be a prerequisite for the transport
of the TNF transcript from the nucleus to the cytoplasm and is therefore essential for LPS-induced production of TNF [42].

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Fig. 2. A) Schematic summary of the TLR4 signaling in macrophages and the control of LPS induced activation of NF-B and IRF3 by MK2 and MK3 as well its impact on subsequent
gene expression. LPS results in the activation of MyD88-dependent signaling that mediates activation of MAPK including Erk1/2, JNK and p38MAPK (Erk1/2 and JNK are not depicted
in the scheme) and activation of the NF-B signaling. TLR4-mediated activation of TRIF dependent signaling occurs subsequent to dynamin-dependent internalization of TLR4 and
subsequent recruitment of TRAM and leads to late phase activation of MAPK family members (not integrated into the scheme) and NF-B as well as to the activation of interferon
response factor (IRF)3 together with NF-B required for the transcriptional regulation of TRIF dependent genes such as the IFN gene. MK2 is required for undisturbed NF-B- and
IRF3-dependent signal transduction and gene expression as it neutralizes inhibitory effects of MK3 on nuclear translocation of NF-B as well as on IRF3 function. In contrast to this
the closely related iso-enzymes MK2 and MK3 cooperatively regulate transcript stability or translation of cytokines such as of TNF or IL-10, whereby stability of the IL-10 transcript
is exclusively controlled by MK2. Apart from the p38MAPK-pathway, the release of IFN and subsequent activation of IFNAR1 is required for LPS-induced production of IL-10 and IL10 dependent activation of STAT3 which in turn is also involved in the regulation of LPS-induced expression of SOCS3. For B) and C) BMDM were prepared from MK2/, MK2/3/
or wild-type mice and subsequently stimulated with 100 ng/ml LPS for 16 h. Thereafter supernatants were collected and analyzed for production of B) IFN and C) IL-10 using ELISA
according to the manufacturer's instructions. Data from at least 3 independent experiments are demonstrated. D) In order to show that LPS-induced STAT3 activation in macrophages decient for both MK2 and MK3 (MK2/3/) is IFNAR dependent BMDM were prepared from MK2/3/ and wild-type mice and pre-treated with 1 g/ml of an IFNAR1
antagonizing antibody or respective isotype control as depicted. After an incubation period of 2 h cells were treated with 100 ng/ml LPS for the indicated time points and total protein lysates were analyzed for STAT3 tyrosine phosphorylation as outlined in the legend in Fig. 1. For E) immortalized bone marrow derived macrophages from MK2/, MK2/3/
or wild-type mice were treated with LPS 100 ng/ml and after a time period of 2 h total RNA was prepared and analyzed for transcript abundance of DUSP1 by RT-PCR using the
primer sequences (sense 5-GCG CTC CAC TCA AGT CTT CT-3; antisense 5-AGT ACT CAG GGG GAG GCT GA-3). The specicity of the RT-PCR was controlled by no template and
no reverse-transcriptase control. Semi-quantitative PCR results were obtained using the CT method. As control gene SDHA was used (primer sequences described in [56]). Threshold values were normalized to SDHA. Data from at least three independent experiments are presented as means plus standard error of means (SEM).

J.G. Bode et al. / Cellular Signalling 24 (2012) 11851194

Although all three groups of MAP-kinases have been demonstrated to be involved in regulation of the inammatory macrophage response towards LPS the published evidence so far suggests that in
particular the p38 MAPK pathway is critical for normal immune and
inammatory response and plays a major role in regulation of inammatory mediator release in macrophages in vivo [23]. p38 MAPK belongs to the p38 MAPK subfamily of MAPK further comprising
p38 MAPK, p38 MAPK and p38 MAPK with p38 MAPK and p38 MAPK
being ubiquitously expressed while the other two show a more tissue
specic expression pattern. Since p38 MAPK is generally expressed at
much higher levels than the p38 MAPK isoform most of the published
literature refers to the p38 MAPK isoform. Apart from its central role
in regulation of immune- and inammatory processes data from
mice with targeted deletion of the p38 MAPK gene indicate that
p38 MAPK is crucial for embryonic development and involved into
several pathologies including cancer, heart and neurodegenerative
diseases [23]. That p38 MAPK is indeed a critical factor for the LPSinduced inammatory macrophage response was conrmed by a recent study using mice with macrophage specic deletion of
p38 MAPK. These mice are largely protected against an otherwise lethal dose of LPS, showing an impaired production of proinammatory cytokines, particularly TNF, IL-12 and IL-18 [43].
Moreover, this study approved that activation of MK2 in response to
LPS is mainly, but not exclusively, mediated via activation of
p38 MAPK. Interestingly, LPS-induced transactivation of CREB and C/
EBP but not of AP1 and NF-B is almost completely abolished in
p38 MAPK decient macrophages [43], suggesting that these factors
play a role for the transcriptional regulation of LPS-induced gene expression by p38 MAPK. This is in particular since in macrophages both,
CREB and C/EBP have been suggested to be important for the LPSinduced transcriptional regulation of TNF, IL-12 and (reported only
for C/EBP) IL-6 gene expression [4448]. A more recent report further demonstrated that p38 MAPK-dependent activation of CREB is
TRAM/TRIF and MyD88 independent but requires the recruitment of
MAL, further involving TNF receptor associated factor (TRAF)6 and
Pellino3. In this pathway MK2 has been suggested to be the downstream mediator of p38 MAPK that controls CREB activation and mediates gene expression such as IL-10 and cyclooxygenase (COX)2 [49].
Although deletion of TRIF does not result in an abrogation of LPSinduced p38 MAPK-activation, a more detailed analysis revealed that
TRIF is of particular importance for maintaining activation of the
MAPKs p38 MAPK, JNK and Erk1/2 at late time points. Notably, the
TRIF-dependent late phase activation of the p38 MAPK/MK2 pathway
has been demonstrated to be essential for translational control of
TNF production [50]. Another molecule, which appears to be implicated in regulation of LPS-induced activation of the p38 MAPK pathway
and posttranscriptional control of cytokine gene expression, is the
IL-1 receptor associated kinase (IRAK)2, which LPS-dependently interacts with the two major upstream activators of the p38 MAPK the
MAPK-kinases (MKK)3 and 6 as well as with MK2 [51] the downstream target of p38 MAPK.
Apart from the aforementioned ndings, p38 MAPK further targets
several other protein kinases including MK3 and the mitogen and
stress activated kinases (MSK)1 and 2, from which MSK1 and 2 are
considered to be involved in transcriptional regulation of LPSinduced gene expression, including the IL-1 receptor antagonist
[52]. Thereby, MSKs integrate signals not only from p38 MAPK, but
also from Erk1/2, which is activated by LPS via the serine/threonine
kinase Tpl2 a pathway essentially required for LPS-induced COX2
gene expression [53]. p38 MAPK further phosphorylates and/or interacts with a heterogeneous group of cytosolic proteins that regulate
processes as diverse as protein ubiquitination, degradation and localization, mRNA-stability, endocytosis, apoptosis, cytoskeleton dynamics or cell migration. Additionally p38 MAPK phosphorylates and
activates several nuclear targets such as the transcription factors
ATF1, ATF2, Sap1 (SRF accessory protein 1), C/EBP (CCAAT/

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enhancer-binding protein), C/EBP-homologous protein (CHOP) and

upstream stimulatory factor (USF)1 [22,54].
A strong body of evidence suggests that among these different factors, MK2 particularly is central to the regulation of the LPS-induced
expression of inammatory factors. Accordingly, MK2-decient mice
are largely resistant towards an otherwise lethal challenge with LPS.
This was suggested to be particularly due to the fact that the LPSinduced production of TNF is almost completely abrogated in
MK2-decient mice [55]. Apart from TNF, MK2 appears to be likewise critical for the regulation of a variety of different other mediators
and molecules involved in the regulation of the inammatory macrophage response towards LPS. Hence, in addition to TNF, the production of IL-6, IL-10 and IFN and to a lesser extent of IL-1 was largely
impaired in MK2-decient spleen cells [55]. Likewise in macrophages
the production of IFN (Fig. 2B and [56]), IL-10 (Fig. 2C and [56]), or
Oncostatin M (own unpublished observations) is also MK2dependent. Thereby, MK2 regulates cytokine expression at different
levels, including CREB- and C/EBP-mediated transcriptional regulation, but also regulation of transcript stability and its translation
[22,57,58]. Thus, LPS regulates the transcript stability of TNF
[5962] and IL-10 [56,63] via activation of the p38 MAPK/MK2 pathway, which further involves the AU-rich element binding, CCCH zinc
nger protein tristetratprolin (TTP) and blocks the TTP-directed
mRNA decay by inhibiting the recruitment of the deadenylase CAF1
(CCR4-associated factor 1) [6165]. The p38 MAPK/MK2 pathway not
only inuences the afnity of TTP towards its target mRNAs and subsequent RNA degradation [61,66,67] but also controls the expression
of TTP mRNA and protein [61]. Correspondingly, MK2-deciency results in an enhanced mRNA binding of TTP and subsequent destabilization of TNF mRNA and an alleviated inammatory response [59],
whereas the lack of TTP stabilizes the TNF transcript and augments
the inammatory response [68]. The fact that the lack of both TTP and
MK2 results in a phenotype similar to the TTP knock out indicates that
MK2 acts upstream of TTP [59]. Other mRNA binding proteins that
have been suggested to be inuenced by MK2 are the AU-rich element binding factors AUF1 [69], hnRNP A0 [70], butyrate response
factor (BRF)1 [71], poly(A)-binding protein (PABP)1 [72], while for
example p38 MAPK-mediated mRNA binding of the ARE-binding protein KRSP is independent from MK2 [73]. The different RNA binding
proteins are not always direct substrates of MK2 but may be also indirectly inuenced by MK2. Hence, for example, recent evidence suggest that the p38 MAPK/MK2 pathway enhances proteolytic destruction
of the RNA destabilizing protein AUF1 via MK2-mediated phosphorylation of the chaperone Hsp27 resulting in an increased transcript stability of ARE containing mRNAs [69]. Apart from enhancing transcript
stability by ameliorating the RNA destabilizing activity of TTP and
AUF1, MK2 may further enhance the stability of selected transcripts
including that of TNF through enhancement of the activity of RNA
stabilizing factors such as hnRNP A0 [70].
Most interestingly, the RNA binding activity of TTP is targeted not
only by stimuli that promote inammatory cytokine production, but
also by IL-10, which TTP-dependently mediates enhanced degradation of the transcripts of pro-inammatory cytokines. This involves
IL-10-induced STAT3-mediated up-regulation of TTP expression and
simultaneous down-regulation of late phase p38 MAPK activity, resulting in an enhanced TTP-mediated degradation of the transcripts of
pro-inammatory cytokines [74]. Thereby, IL-10 mediates inhibition
of late phase p38 MAPK-phosphorylation through an enhanced expression of the dual specic phosphatase (DUSP)1 that dephosphorylates
p38 MAPK [74] and which, at least in macrophages, is also MK2dependently regulated in response to LPS (Fig. 2E) and in response
to PGN [75]. Of note, expression of the IL-10 transcript itself is in
turn regulated by TTP, which enhances the deadenylation of its 3
UTR, a process that is counter-regulated by activation of p38 MAPK
[63]. Altogether one may conclude from these data that the
p38 MAPK/MK2/TTP pathway owns a key position in orchestrating

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inammatory cytokine expression in response to LPS as well as its

successional shut down and that in this context the expression level
of TTP and the degree of its phosphorylation may represent a kind
of molecular switch.
4. Regulation of cytokine secretion by LPS in macrophages
A primary function of activated macrophages is the rapid and
abundant secretion of cytokines and chemokines upon activation by
different TLRs. Transport of the synthesized cytokines and chemokines to the plasma membrane and subsequent secretion requires
substantial up-regulation of protein trafcking and deployment of
the vesicle membrane to the cell surface. Macrophages undergo a dramatic increase in exocytotic trafcking activity upon activation by LPS
[76] suggesting that TLR4 directly triggers the signaling events that
control trafcking of exocytotic vesicles. The multiple steps of intracellular protein transport in small carrier vesicles from their place of
synthesis to the cell surface have been extensively described
[77,78]. However, the molecular targets, which regulate the trafc
machinery leading to mediator release in response to TLR4 ligands
such as LPS, are only partially known and subjects of ongoing research. One of the secretory pathways which has been extensively investigated is the secretory pathway of the newly synthesized
transmembrane form of TNF. In macrophages, the major part of
TNF secreted in response to LPS derives from enhanced transcriptional activation of the TNF gene and subsequent biosynthesis
[79]. Only a minor part of the TNF secreted upon activation derives
from intracellular stores. The newly synthesized TNF rapidly accumulates in great concentrations in the perinuclear Golgi complex,
being maximal within 2 h after stimulation with LPS [80,81] and is released in a battery of small vesicular carriers leaving the trans-Golgi
network in its 26 kDa transmembrane precursor form [76,80]. Thereby, the early phase of TNF export in response to LPS is regulated by
golgins, long coiled-coil proteins localized to distinct membrane domains of the trans-Golgi network [82,83]. The golgin p230, an essential component of the tubules at the trans-Golgi network, is a key
mediator of LPS-induced TNF secretion as it facilitates its postGolgi transport [82]. While p230 protein levels are not inuenced
by LPS, other components, such as SNARES (soluble Nethylmaleimide-sensitive factor attachment receptor) and RabGTPases, demonstrated to be involved in TNF trafcking are target
genes up-regulated in response to LPS [77]. Both RabGTPases and
SNARE proteins are essential components of the membrane fusion
complex [78,84]. In particular, the SNARE proteins Vamp3, Vti1b, syntaxins 4 and 6 as well as the RabGTPase Rab37 play crucial roles in the
docking and fusion of TNF-containing secretory vesicles at the macrophage cell surface in response to LPS. Their enhanced expression in
response to LPS augments the delivery of TNF to the cell surface and
enhances its exocytosis [76,81,85]. Another protein, which plays a
role for the LPS-induced release of TNF is the PI3K isoform p110
that translocates to the Golgi upon activation by LPS and controls
the membrane fusion machinery [86]. Most interestingly TNF is
not delivered randomly to locations at the cell surface but rather specically delivered to sites of phagocytic cup formation [76], where its
membrane bound precursor form is processed to its soluble form of
17 kDa upon cleavage by TACE (TNF converting enzyme) [87]. This
TACE-mediated cleavage of the TNF precursor is controlled by the
lipid hydrolase ASMase (acid sphingomyelinase) activated in response to LPS [88].
With respect to the complex regulation of LPS-induced secretion
of TNF it should be noted that p38 MAPK is also involved in modulation of membrane trafc via the regulation of the Rab GTPases Rab5
and Rab7, key coordinators of endocytic trafcking, suggesting a
cross-talk between the p38 MAPK-dependent stress response and the
intra-cellular trafcking machinery [89,90]. Hence, one may speculate
that, apart from being essentially involved in transcriptional,

posttranscriptional and translational control of LPS-inducible gene

expression, p38 MAPK also plays a role in the regulation of trafcking
events, which are involved in LPS-mediated cytokine secretion.
5. Regulation of the inammatory macrophage response
through the cross-talk between STAT3- and p38 MAPK-mediated
signal-transduction
As outlined above macrophages release pro- as well as antiinammatory mediators and once activated are subjected to a tight
feedback control to prevent an overshooting response with devastating consequences. However, apart from limiting the inammatory response, the regulatory processes must also warrant that the
inammatory response is not untimely terminated as this might result in a failure of anti-infectious effector mechanisms and tissue repair. Hence, a sufcient inammatory response essentially requires
a balanced and well-ordered succession of pro- and antiinammatory signaling events [41,91].
In this context IL-10 is considered to be the most important mediator of anti-inammatory activities. It belongs to a family of cytokines, which apart from IL-10 comprises the IL-20 subfamily of
cytokines (IL-19, IL-20, IL-22, IL-24 and IL-26) and the more distantly
related group of type III interferons (IL-28A, IL-28B, and IL-29). Originally described as a secreted cytokine synthesis inhibitory factor
(CSIF), IL-10 is a general suppressive cytokine, known to regulate
and repress the production of pro-inammatory cytokines, such as
TNF, IL-1, IL-12 or IFN during the recovery phase of infections
[92]. IL-10 is expressed by a variety of cells of the innate and adaptive
immune system including neutrophils, dendritic cells, macrophages
and is crucial for the suppressive functions of regulatory T-cells. Acting as a paracrine feedback loop macrophage-derived IL-10 further
inhibits the differentiation of neighboring cells into classically activated macrophages, enabling the macrophage population to be selfregulating [93]. It is therefore considered to be a key mediator during
the resolution phase of inammation. Consistently, targeted disruption of the IL-10 gene results in spontaneous development of colitis
[18] and aggravates Con A induced hepatitis [94] as well as liver injury induced by galactosamine and LPS [95]. Moreover, IL-10 is a key
factor to overcome endotoxic shock and sensitization towards LPS,
as IL-10 decient mice are highly sensitive towards LPS and extremely vulnerable towards a generalized Schwartzman reaction [17].
5.1. STAT3 is the key effector molecule of IL-10 action
Binding of IL-10 to the IL-10 receptor complex, comprising the IL10 receptor (IL-10R)1 subunit that binds IL-10 with high afnity and
the low afnity subunit IL-10R2, results in activation of intra-cellular
signal-transduction, which is mainly transmitted via Jak1-mediated
activation of STAT3, which has been identied as the key mediator
of the anti-inammatory effects of IL-10 [16,96,97]. That STAT3 is crucial for the transmission of anti-inammatory signals in macrophages
and neutrophils in vivo has been impressively demonstrated in mice
with macrophage-/neutrophil-specic deletion of the STAT3 gene,
which spontaneously develop an enterocolitis and are highly susceptible towards LPS-mediated shock and septic peritonitis [16,98100]
a phenotype which closely resembles to that reported for IL-10decient mice. Consistently, the overwhelming inammatory response observed in animals with macrophage-/neutrophil-specic
deletion of the STAT3 gene was mainly due to the fact that, in the absence of STAT3, IL-10 is incapable to mediate its suppressive effects
on macrophages [16]. This results in an enhanced LPS- or infectioninduced production of inammatory cytokines, including TNF, IL1, IL-6, IL-12, IFN but also of IL-10 itself [16,99]. Accordingly, gene
expression studies likewise indicate that IL-10 essentially requires
STAT3 to affect the activation program triggered by LPS [19]. This is
paralleled by an impaired bactericidal activity of STAT3 decient

J.G. Bode et al. / Cellular Signalling 24 (2012) 11851194

macrophages resulting in a reduced ability to clear bacterial infections. An observation that indicates, that activation of STAT3 does
not only temper inammatory cytokine production but also mediates
substantial functional changes in macrophages [99].
5.2. In macrophages SOCS3 prevents other STAT3-activating cytokines
from mediating IL-10-like anti-inammatory effects
Importantly, not all immune-regulatory cytokines that activate
STAT3 mediate IL-10-like anti-inammatory effects. In fact, the vast
majority of STAT3-activating cytokines, such as for example IL-6 or
IFN, rather mediate pro- than anti-inammatory effects. The reason
for these divergent biological consequences of STAT3-activation in
response to IL-10 on the one hand and cytokines such as IL-6 or IFN
on the other hand, is not completely understood. However, several
evidences suggest that the time course of STAT3 activation in response to the respective cytokine as well as the pattern of co-acting
signals plays a role [101103]. In this context, the sensitivity of the
respective cytokine receptors towards suppressor of cytokine signaling (SOCS)3 is of particular importance [103]. SOCS proteins are a
family of potent endogenous inhibitors that are of key importance
for limiting STAT-mediated signal-transduction. These proteins are
induced by STAT-activating cytokines, and therefore act in a classical
negative-feedback loop. In addition, a variety of other stimuli, including
TLR ligands [102,104] or pro-inammatory mediators such as IL-1 or
TNF [102,105107] cell type dependently also induce or enhance expression of SOCS proteins, thereby impeding STAT-dependent cytokine
signaling.
SOCS proteins mediate their effects either by inhibition of the activity of Janus kinases (JAK) through their kinase inhibitory region
(KIR) or by ubiquitin mediated degradation of the signaling complex
[108]. Thereby, the target of each SOCS protein is determined by its
central Src homology (SH) domain, enabling for example SOCS3 to become recruited to the cytoplasmic tail of the activated gp130 signaltransducing subunit of the IL-6 receptor complex via phosphotyrosine/SH2 domain interactions at tyrosine residue 757. This tyrosine
757 mediated receptor-recruitment of SOCS3 has been demonstrated
to be a prerequisite for the inhibition of gp130-mediated activation of
STAT3 [109]. Furthermore it also plays a role for mediating the inhibitory effect of TNF on IL-6-induced STAT3 activation [105] since mutation of this tyrosine residue to phenylalanine abrogates the
inhibitory effects of TNF on gp130-induced STAT3 activation.
Hence, in macrophages the time course and the amplitude of IL-6induced STAT3-activation are largely determined by the intracellular
protein levels of SOCS3 and by the variety of different factors that inuence SOCS3-expression [101,102,110]. Consistently, inammatory
mediators such as LPS or TNF induce SOCS3 expression in macrophages and almost completely block STAT3 activation in response to
stimulation with IL-6 [102,105] or IFN (Fig. 1B). In contrast to this,
the IL-10-induced STAT3 activation is insensitive towards the inhibitory effects of SOCS proteins [103], resulting in a sustained STAT3 activation, which is even rather enhanced than diminished by costimulation with LPS (Fig. 1B). In line with these observations, IL-10
has been identied as the major factor that mediates the delayed activation of STAT3 that can be observed in macrophages upon stimulation with LPS for more than approximately 1 h [111]. Hence, SOCS3
appears to be a key regulator that prevents cytokines such as IL-6
from untimely mediating IL-10-like suppressive effects on inammatory cytokine response via induction of a sustained STAT3-activation.
That this is indeed the case has been further substantiated in macrophages prepared from mice with macrophage-/neutrophil-specic
deletion of the SOCS3 gene. In these macrophages IL-6 induces a sustained STAT3 activation and mediates IL-10-like anti-inammatory
effects, which may also contribute to the fact that these mice are resistant towards LPS-induced septic shock [101]. Most interestingly,
mice in which enhanced and prolonged STAT3 activation is not

1191

restricted to macrophages and neutrophils show a converse reaction

towards LPS. Thus, mice expressing a mutated gp130 receptor subunit, which is incapable to recruit SOCS3 to gp130, are hypersensitive
towards LPS although they show an enhanced and prolonged STAT3
activation if determined in liver tissue. This hypersensitivity towards
LPS was demonstrated to be due to an enhanced LPS-induced production of IL-6 and was alleviated through genetic reduction of STAT3 activity or through inhibition of IL-6 trans-signaling [112]. These data
suggest that the anti-inammatory action of enhanced and sustained
STAT3 activation is restricted to innate immune cells and in particular
to macrophages and neutrophils, while in other cell types enhancement of the STAT3 signal may have controversial effects and rather
act as an enhancer of inammation e.g. by up-regulation of the production of cytokines such as in particular IL-6.
5.3. The p38 MAPK pathway owns a key position in regulation of the
inammatory response by orchestrating pro-inammatory as well as
anti-inammatory effector mechanisms
Altogether the data from the current literature provide clear evidence, that in macrophages SOCS3 is of key importance in preventing
IL-6 from mediating IL-10 like signals and that this mechanism is utilized by pro-inammatory mediators such as LPS or TNF to avert an
untimely activation of STAT3-mediated anti-inammatory effector
mechanisms. Apart from STAT3 and specicity protein (SP)3, which
both are important transcriptional regulators of SOCS3 expression
[108,113,114], strong evidence indicates that the p38 MAPK/MK2 pathway also plays an essential role in regulating SOCS3 expression in response to TLR ligands and TNF [102,104,105,107] but also in
response to IL-6 [115]. Thus, in macrophages inhibition of the
p38 MAPK pathway results in a strong inhibition of LPS or TNFinduced SOCS3 expression and almost completely neutralizes the inhibitory effects of LPS or TNF on IL-6-induced activation of STAT3
[102,105]. A more detailed analysis further revealed that induction
of SOCS3 expression is indeed necessary for these inhibitory effects
of LPS and TNF on IL-6-induced STAT activation, although not sufcient for these effects. Moreover, activation of p38 MAPK also negatively regulates IL-6 signaling independent of its parallel and necessary
action to induce SOCS3 expression [116]. With respect to this it is interesting to note that in hepatocytes and broblasts IL-1-induced
activation of MK2 and MK2-mediated phosphorylation of gp130 at
the serine residue 782 results in an internalization and subsequent
degradation of gp130 [117]. This observation may also explain the reduction in total cellular levels of gp130 observed in LPS- or TNFtreated macrophages [116], which possibly is likewise mediated via
activation of the p38 MAPK/MK2 pathway.
While in the case of TNF, regulation of SOCS3 expression includes MK2-mediated stabilization of the transcript [107] it is not
clear at which level the p38 MAPK pathway is involved in LPSinduced SOCS3 expression. In line with recent reports our own observations suggest that LPS mainly controls SOCS3 expression at the
level of transcription and, in contrast to TNF, it does not involve
modulation of transcript stability (unpublished observation). Thereby, LPS-treatment of macrophages led to the acetylation of the histones H3 and H4 on the SOCS3 promoter and the recruitment of the
transcription factors STAT3, ATF-2, p300 and CREB-binding protein
as well as of the hetero-dimeric transcription factor AP-1, that comprises c-Fos and c-Jun [118,119]. Moreover, production of IL-10 and
IL-10-induced activation of STAT3 is necessary for sufcient SOCS3
expression in response to LPS, indicating that regulation of SOCS3 in
response to LPS involves the activation of IL-10-mediated feedback
loops [119].
Most interestingly, induction of IL-10 production upon stimulation
with LPS itself also depends on STAT3 and essentially requires the activation of the p38 MAPK pathway and p38 MAPK-mediated regulation of
MK2 as well as inhibition of TTP-directed decay of the IL-10 transcript

1192

J.G. Bode et al. / Cellular Signalling 24 (2012) 11851194

[56,63,120124]. Accordingly, enhanced activation of p38 MAPK in the

absence of its negative regulator the dual specic phosphatase
(DUSP)1 (also termed as MKP1) results in an increased LPS-induced
cytokine production including IL-10 [125127]. The relevance of the
p38 MAPKpathway for induction of IL-10 expression has been further
corroborated by a more recent report which also suggested that in addition to the p38 MAPK pathway activation of NF-B is critical [128] and
that both p38 MAPK/MK2- and NF-B-dependent signaling are regulated by the p40 isoform of the RNA binding protein AUF1 [122]. However, LPS-induced IL-10 expression occurs indirectly and requires
activation of the IFN alpha receptor (IFNAR)1 and the sequential progression of type I IFN induction followed by IL-27 activation in an autocrine/paracrine manner [21,129]. Consistently, LPS-induced
activation of STAT3, which is mainly IL-10-mediated, is almost
completely abrogated in IFNAR1 decient macrophages [21,56]. This
also correlates with the different time courses of IFN and IL-10 production in LPS-treated macrophages, with IFN reaching maximal
levels at a time point where IL-10 production is starting to increase
(Fig. 1C). While the role of type I interferons and the relevance of
IFNAR1-mediated signaling for LPS-induced production of IL-10 and
subsequent activation of STAT3 is well documented by independent
groups [21,56,129] the data concerning the relevance of IL-27 are
conicting since, at least in monocytes, IL-27 has been also reported
to even strongly suppress the TLR-induced production of IL-10 [130].
Until now it is not understood at which level of the autocrine/
paracrine feedback loops that regulate IL-10 expression in response
to LPS the different intra-cellular signaling pathways are involved in
regulation of LPS-induced IL-10 expression. The results of a recent
study suggested that the p38 MAPK/MK2 pathway and the interrelationship of MK2 with its closely related isoform MK3 is central to
the different regulatory steps engaged in regulation of IL-10 expression in LPS treated macrophages [56]. Thereby, MK2 permits enhanced transcription of IFN gene expression in macrophages by
neutralizing negative regulatory effects of MK3 on NF-B- and IRF3mediated signal-transduction, which in the case of NF-B involves enhanced expression and delayed degradation of IB. Consistently, impaired LPS-induced nuclear translocation of NF-B and function of
IRF3 observed in MK2 decient macrophages recovers upon additional deletion of the MK3 gene. As a result LPS-induced expression of
IFN is reconstituted in MK2/3 / macrophages at the level of transcript [56] as well as on the level of protein (Fig. 2B), which is strongly
suppressed in macrophages that are only decient for MK2 when
compared to respective control cells. This is in contrast to the regulation of IL-10 transcript [56] and protein (Fig. 2C) expression in response to LPS, which requires MK2 activity independent from MK3
for stabilization of the IL-10 transcript [56] and therefore is affected
in both MK2/3 / macrophages and in MK2 / macrophages. Of
note, LPS-induced STAT3 activation is at least in part rescued in macrophages decient for both MK2 and MK3, although in these cells
only the expression of IFN, but not of IL-10, is reconstituted. It is
therefore likely that in the absence of MK2 and MK3 the rescue of
LPS-induced STAT3 activation is due to restored IFN production
and occurs independent from IL-10 [56] which is also reected by
the fact that the time course of STAT3 activation in LPS treated
MK2/3 / macrophages is transient and not sustained as it is the
case in respective control macrophages (Fig. 2D). In support of this
assumption treatment of MK2/3 / macrophages with an IFNAR1 antagonizing antibody almost completely abrogates LPS-induced STAT3
activation (Fig. 2D). Most interestingly, reconstitution of IFN production and of IFN-mediated STAT3 activation in MK2/3 / macrophages is also accompanied by the reconstitution of other genes such
as DUSP1 (Fig. 2E), which is considered to be responsible for IL-10mediated down-regulation of late phase p38 MAPK activation in LPS
treated macrophages [74]. That the DUSP1 mediated dampening of
p38 MAPK activation may indeed contribute to the anti-inammatory
effector mechanisms of IL-10 becomes evident from the fact that

DUSP1 decient mice exhibit an exacerbated inammatory cytokine

production and increased mortality in response to a challenge with
LPS [125,127], which has been largely attributed to an uncontrolled
activation of the p38 MAPK pathway [126].
Hence, in macrophages the p38 MAPK/MK2/MK3 pathway controls
critical nodes of LPS-signaling and LPS-mediated gene expression of
IFN and regulates the transcript stability of IL-10. It is therefore essential for delayed STAT3 activation in response to LPS driven by a sequential induction of type I IFNs followed by induction and signaling
through IL-10. Moreover, MK2 permits expression of DUSP1, which,
like the IFN gene, in the absence of MK2 is subjected to a negative
control by MK3 (data presented in Fig. 2E). Thus, MK2 and MK3,
which so far appeared as closely-related, cooperatively acting isoenzymes [57,131], also have different regulatory roles, with MK2 regulating gene expression by preventing MK3-mediated negative regulatory effects on NF-B- and IRF3-mediated signal-transduction of LPS
that plays a critical role in LPS-induced gene expression of e.g. IFN.
6. Conclusions and outlook
The different signaling cascades that are activated in macrophages
in response to TLR4 activation, such as the different MAP-kinase family members, the NF-B pathway and the cascade that activates IRF3
is comparably well investigated. Likewise, the different adapters
such as TRAM, TRIF, MAL and MyD88 recruited to the TLR4 receptor
complex have been studied in deeper detail. However, most of the
studies focus on separate pathways and do not sufciently take into
account the complex network of cross-talk between the different
pathways and the impact of the various and undetachable autocrine
and paracrine input that drives macrophage response towards LPS.
A point which becomes even manifold more complex in the context
of bacterial infection as this results in the activating input of a much
broader spectrum of PRRs. Identication of node points within this
complex network that are pivotal for development of the inammatory macrophage response towards one or the other direction is essentially required for the development of novel therapeutic
strategies for treatment of inammatory diseases. Apart from a detailed molecular biological analysis of the cross-talk and the reciprocal interrelationship of the different pathways this requires an
experimentally validated systems biological approach that takes
into account the considerable dynamic complexity of the different
pathways as well as their spatio-temporal compartmentalization. In
this context the construction of respective validated models that are
able to predict behavior of a system as well as the biological responses
is at rst a challenging goal, which has been addressed in recent reports [132134].
As outlined in the present review, in macrophages the p38 MAPK
pathway most likely owns a key position in the orchestration of the
inammatory response and its subsequent IL-10-mediated STAT3dependent resolution. It is necessary for initiation and propagation
of the inammatory macrophage response as it controls the expression of inammatory cytokines including IFN, IFN, TNF, IL-1,
IL-6, IL-12 and OSM at different levels involving regulation of transcription, of transcript stability as well as of translation. Whether it
is also involved in cytokine secretion needs to be established. In addition, it regulates surface expression of cytokine receptors and prevents cytokines, such as IL-6, from eliciting IL-10-like activities
through premature induction of a sustained STAT3 activation. In this
context SOCS3 has been identied as a critical factor, which is
STAT3 and p38 MAPK-dependently regulated and separates SOCS3sensitive signal-transduction of STAT3-activating cytokines from
those which are insensitive towards SOCS3, namely of IL-10.
Apart from driving and maintaining the inammatory macrophage response the p38 MAPK/MK2/MK3 pathway is also essentially
involved in the regulation of the IL-10- and STAT3-dependent resolution phase of the inammatory response as it controls transcriptional

J.G. Bode et al. / Cellular Signalling 24 (2012) 11851194

up-regulation of type I IFN gene expression, which is required for subsequent up-regulation of IL-10 gene expression which is further MK2dependently regulated at the level of transcript stability. In addition,
MK2 and MK3 appear to be further engaged in the regulation of
IB [56], which has been recently recognized as another critical factor, which phosphorylation-dependently is involved in induction of
inammatory gene expression in vivo [135,136] as well as in binding
and negative regulation of NF-B [137139]. As suggested by data
presented herein, apart from the IFN gene, MK2 appears to be further important for neutralizing negative regulatory effects of MK3
on the LPS-induced expression of DUSP1, which also has been demonstrated to be crucial for driving the resolution phase of an inammatory response. Therefore, the elucidation of the exact nature of
the interrelationship between MK2 and MK3 and an in-depth understanding of the molecular mechanisms by which they inuence NFB-, IRF3- and STAT3-dependent signaling is an important goal of future scientic approaches.
Acknowledgment
We especially thank Matthias Gaestel (MHH Hannover) and his
group for providing the MK2 and MK2/3 decient animals and cell
lines and for the very fruitful cooperation and the continuous support
experienced. Thanks also to Marijana Suzanj for her technical assistance. The work discussed herein has been funded by grants from
the Deutsche Forschungsgemeinschaft, in particular by the collaborative research centers, the SFB 575 and the SFB 974. Additional funding
came from the local Forschungskomission of the medical faculty of
the Heinrich-Heine-University and from the BMBF-funded research
network Virtual Liver.
References
[1] T.J. Abernethy, O.T. Avery, The Journal of Experimental Medicine 73 (1941) 173182.
[2] B. Bottazzi, A. Doni, C. Garlanda, A. Mantovani, Annual Review of Immunology
28 (2010) 157183.
[3] J.G. Bode, U. Albrecht, D. Hussinger, P.C. Heinrich, F. Schaper, European Journal
of Cell Biology (2011), doi:10.1016/j.ejcb.2011.09.008.
[4] T. Kawai, S. Akira, Immunity 34 (2011) 637650.
[5] T. Kawai, S. Akira, International Immunology 21 (2009) 317337.
[6] L.A. O'Neill, Immunological Reviews 226 (2008) 1018.
[7] D.M. Bowdish, S. Gordon, Immunological Reviews 227 (2009) 1931.
[8] H.S. Goodridge, A.J. Wolf, D.M. Underhill, Immunological Reviews 230 (2009)
3850.
[9] Y.M. Loo, M. Gale Jr., Immunity 34 (2011) 680692.
[10] A. Takaoka, Z. Wang, M.K. Choi, H. Yanai, H. Negishi, T. Ban, Y. Lu, M. Miyagishi, T.
Kodama, K. Honda, Y. Ohba, T. Taniguchi, Nature 448 (2007) 501505.
[11] T. Burckstummer, C. Baumann, S. Bluml, E. Dixit, G. Durnberger, H. Jahn, M.
Planyavsky, M. Bilban, J. Colinge, K.L. Bennett, G. Superti-Furga, Nature Immunology 10 (2009) 266272.
[12] H. Ishikawa, G.N. Barber, Nature 455 (2008) 674678.
[13] S. Liu, D.J. Gallo, A.M. Green, D.L. Williams, X. Gong, R.A. Shapiro, A.A. Gambotto,
E.L. Humphris, Y. Vodovotz, T.R. Billiar, Infection and Immunity 70 (2002)
34333442.
[14] E. Seki, S. De Minicis, C.H. Osterreicher, J. Kluwe, Y. Osawa, D.A. Brenner, R.F.
Schwabe, Nature Medicine 13 (2007) 13241332.
[15] M. Isogawa, M.D. Robek, Y. Furuichi, F.V. Chisari, Journal of Virology 79 (2005)
72697272.
[16] K. Takeda, B.E. Clausen, T. Kaisho, T. Tsujimura, N. Terada, I. Forster, S. Akira, Immunity 10 (1999) 3949.
[17] D.J. Berg, R. Kuhn, K. Rajewsky, W. Muller, S. Menon, N. Davidson, G. Grunig, D.
Rennick, Journal of Clinical Investigation 96 (1995) 23392347.
[18] R. Kuhn, J. Lohler, D. Rennick, K. Rajewsky, W. Muller, Cell 75 (1993) 263274.
[19] R. Lang, D. Patel, J.J. Morris, R.L. Rutschman, P.J. Murray, Journal of Immunology
169 (2002) 22532263.
[20] R. Lang, Immunobiology 210 (2005) 6376.
[21] E.Y. Chang, B. Guo, S.E. Doyle, G. Cheng, Journal of Immunology 178 (2007)
67056709.
[22] M. Cargnello, P.P. Roux, Microbiology and Molecular Biology Reviews 75 (2011)
5083.
[23] A. Cuadrado, A.R. Nebreda, Biochemical Journal 429 (2010) 403417.
[24] A. Poltorak, X. He, I. Smirnova, M.Y. Liu, C. Van Huffel, X. Du, D. Birdwell, E.
Alejos, M. Silva, C. Galanos, M. Freudenberg, P. Ricciardi-Castagnoli, B. Layton,
B. Beutler, Science 282 (1998) 20852088.
[25] A. Poltorak, P. Ricciardi-Castagnoli, S. Citterio, B. Beutler, Proceedings of the National Academy of Sciences of the United States of America 97 (2000) 21632167.

1193

[26] B. Lemaitre, E. Nicolas, L. Michaut, J.M. Reichhart, J.A. Hoffmann, Cell 86 (1996)
973983.
[27] L.A. O'Neill, Science's STKE (2000) re1.
[28] E.M. Palsson-McDermott, L.A. O'Neill, Immunology 113 (2004) 153162.
[29] R. Shimazu, S. Akashi, H. Ogata, Y. Nagai, K. Fukudome, K. Miyake, M. Kimoto,
The Journal of Experimental Medicine 189 (1999) 17771782.
[30] M. Kobayashi, S. Saitoh, N. Tanimura, K. Takahashi, K. Kawasaki, M. Nishijima, Y.
Fujimoto, K. Fukase, S. Akashi-Takamura, K. Miyake, Journal of Immunology 176
(2006) 62116218.
[31] Y. Nagai, S. Akashi, M. Nagafuku, M. Ogata, Y. Iwakura, S. Akira, T. Kitamura, A.
Kosugi, M. Kimoto, K. Miyake, Nature Immunology 3 (2002) 667672.
[32] P.Y. Perera, T.N. Mayadas, O. Takeuchi, S. Akira, M. Zaks-Zilberman, S.M. Goyert,
S.N. Vogel, Journal of Immunology 166 (2001) 574581.
[33] T. Kawai, O. Adachi, T. Ogawa, K. Takeda, S. Akira, Immunity 11 (1999) 115122.
[34] E.F. Kenny, L.A. O'Neill, Cytokine 43 (2008) 342349.
[35] S.M. Miggin, E. Palsson-McDermott, A. Dunne, C. Jefferies, E. Pinteaux, K.
Banahan, C. Murphy, P. Moynagh, M. Yamamoto, S. Akira, N. Rothwell, D.
Golenbock, K.A. Fitzgerald, L.A. O'Neill, Proceedings of the National Academy
of Sciences of the United States of America 104 (2007) 33723377.
[36] T. Kawai, O. Takeuchi, T. Fujita, J. Inoue, P.F. Muhlradt, S. Sato, K. Hoshino, S.
Akira, Journal of Immunology 167 (2001) 58875894.
[37] M. Yamamoto, S. Sato, K. Mori, K. Hoshino, O. Takeuchi, K. Takeda, S. Akira, Journal of Immunology 169 (2002) 66686672.
[38] J.C. Kagan, T. Su, T. Horng, A. Chow, S. Akira, R. Medzhitov, Nature Immunology 9
(2008) 361368.
[39] M.B. Fessler, J.S. Parks, Journal of Immunology 187 (2011) 15291535.
[40] M. Yamamoto, S. Sato, H. Hemmi, S. Uematsu, K. Hoshino, T. Kaisho, O. Takeuchi,
K. Takeda, S. Akira, Nature Immunology 4 (2003) 11441150.
[41] B. Beutler, K. Hoebe, X. Du, R.J. Ulevitch, Journal of Leukocyte Biology 74 (2003)
479485.
[42] C.D. Dumitru, J.D. Ceci, C. Tsatsanis, D. Kontoyiannis, K. Stamatakis, J.H. Lin, C.
Patriotis, N.A. Jenkins, N.G. Copeland, G. Kollias, P.N. Tsichlis, Cell 103 (2000)
10711083.
[43] Y.J. Kang, J. Chen, M. Otsuka, J. Mols, S. Ren, Y. Wang, J. Han, Journal of Immunology 180 (2008) 50755082.
[44] R. Pope, S. Mungre, H. Liu, B. Thimmapaya, Cytokine 12 (2000) 11711181.
[45] D.I. Tai, S.L. Tsai, Y.M. Chen, Y.L. Chuang, C.Y. Peng, I.S. Sheen, C.T. Yeh, K.S.
Chang, S.N. Huang, G.C. Kuo, Y.F. Liaw, Hepatology 31 (2000) 656664.
[46] A. Zagariya, S. Mungre, R. Lovis, M. Birrer, S. Ness, B. Thimmapaya, R. Pope, Molecular and Cellular Biology 18 (1998) 28152824.
[47] H.M. Hu, Q. Tian, M. Baer, C.J. Spooner, S.C. Williams, P.F. Johnson, R.C. Schwartz,
Journal of Biological Chemistry 275 (2000) 1637316381.
[48] S.E. Plevy, J.H. Gemberling, S. Hsu, A.J. Dorner, S.T. Smale, Molecular and Cellular
Biology 17 (1997) 45724588.
[49] M. Mellett, P. Atzei, R. Jackson, L.A. O'Neill, P.N. Moynagh, Journal of Immunology 186 (2011) 49254935.
[50] P. Gais, C. Tiedje, F. Altmayr, M. Gaestel, H. Weighardt, B. Holzmann, Journal of
Immunology 184 (2010) 58425848.
[51] Y. Wan, H. Xiao, J. Affolter, T.W. Kim, K. Bulek, S. Chaudhuri, D. Carlson, T.
Hamilton, B. Mazumder, G.R. Stark, J. Thomas, X. Li, Journal of Biological Chemistry 284 (2009) 1036710375.
[52] J. Darragh, O. Ananieva, A. Courtney, S. Elcombe, J.S. Arthur, Biochemical Journal
425 (2010) 595602.
[53] A.G. Eliopoulos, C.D. Dumitru, C.C. Wang, J. Cho, P.N. Tsichlis, EMBO Journal 21
(2002) 48314840.
[54] A. Cuenda, S. Rousseau, Biochimica et Biophysica Acta 1773 (2007) 13581375.
[55] A. Kotlyarov, A. Neininger, C. Schubert, R. Eckert, C. Birchmeier, H.D. Volk, M.
Gaestel, Nature Cell Biology 1 (1999) 9497.
[56] C. Ehlting, N. Ronkina, O. Bohmer, U. Albrecht, K.A. Bode, K.S. Lang, A. Kotlyarov,
D. Radzioch, M. Gaestel, D. Hussinger, J.G. Bode, Journal of Biological Chemistry
286 (2011) 2411324124.
[57] M. Gaestel, Nature Reviews. Molecular Cell Biology 7 (2006) 120130.
[58] R. Winzen, M. Kracht, B. Ritter, A. Wilhelm, C.Y. Chen, A.B. Shyu, M. Muller, M.
Gaestel, K. Resch, H. Holtmann, EMBO Journal 18 (1999) 49694980.
[59] E. Hitti, T. Iakovleva, M. Brook, S. Deppenmeier, A.D. Gruber, D. Radzioch, A.R.
Clark, P.J. Blackshear, A. Kotlyarov, M. Gaestel, Molecular and Cellular Biology
26 (2006) 23992407.
[60] P. Anderson, Nature Immunology 9 (2008) 353359.
[61] E. Carballo, H. Cao, W.S. Lai, E.A. Kennington, D. Campbell, P.J. Blackshear, Journal
of Biological Chemistry 276 (2001) 4258042587.
[62] H. Cao, F. Dzineku, P.J. Blackshear, Archives of Biochemistry and Biophysics 412
(2003) 106120.
[63] C. Tudor, F.P. Marchese, E. Hitti, A. Aubareda, L. Rawlinson, M. Gaestel, P.J.
Blackshear, A.R. Clark, J. Saklatvala, J.L. Dean, FEBS Letters 583 (2009) 19331938.
[64] F.P. Marchese, A. Aubareda, C. Tudor, J. Saklatvala, A.R. Clark, J.L. Dean, Journal of
Biological Chemistry 285 (2010) 2759027600.
[65] N. Ronkina, M.B. Menon, J. Schwermann, C. Tiedje, E. Hitti, A. Kotlyarov, M.
Gaestel, Biochemical Pharmacology 80 (2010) 19151920.
[66] S.L. Clement, C. Scheckel, G. Stoecklin, J. Lykke-Andersen, Molecular and Cellular
Biology 31 (2011) 256266.
[67] C.A. Chrestensen, M.J. Schroeder, J. Shabanowitz, D.F. Hunt, J.W. Pelo, M.T.
Worthington, T.W. Sturgill, Journal of Biological Chemistry 279 (2004)
1017610184.
[68] G.A. Taylor, E. Carballo, D.M. Lee, W.S. Lai, M.J. Thompson, D.D. Patel, D.I.
Schenkman, G.S. Gilkeson, H.E. Broxmeyer, B.F. Haynes, P.J. Blackshear, Immunity
4 (1996) 445454.

1194

J.G. Bode et al. / Cellular Signalling 24 (2012) 11851194

[69] A.M. Knapinska, F.M. Gratacos, C.D. Krause, K. Hernandez, A.G. Jensen, J.J.
Bradley, X. Wu, S. Pestka, G. Brewer, Molecular and Cellular Biology 31 (2011)
14191431.
[70] S. Rousseau, N. Morrice, M. Peggie, D.G. Campbell, M. Gaestel, P. Cohen, EMBO
Journal 21 (2002) 65056514.
[71] S. Maitra, C.F. Chou, C.A. Luber, K.Y. Lee, M. Mann, C.Y. Chen, RNA 14 (2008)
950959.
[72] F. Bollig, R. Winzen, M. Gaestel, S. Kostka, K. Resch, H. Holtmann, Biochemical
and Biophysical Research Communications 301 (2003) 665670.
[73] R. Winzen, D. Wallach, H. Engelmann, Y. Nophar, C. Brakebusch, O. Kemper, K.
Resch, H. Holtmann, Journal of Immunology 148 (1992) 34543460.
[74] B. Schaljo, F. Kratochvill, N. Gratz, I. Sadzak, I. Sauer, M. Hammer, C. Vogl, B.
Strobl, M. Muller, P.J. Blackshear, V. Poli, R. Lang, P.J. Murray, P. Kovarik, Journal
of Immunology 183 (2009) 11971206.
[75] J.H. Hu, T. Chen, Z.H. Zhuang, L. Kong, M.C. Yu, Y. Liu, J.W. Zang, B.X. Ge, Cellular
Signalling 19 (2007) 393400.
[76] R.Z. Murray, J.G. Kay, D.G. Sangermani, J.L. Stow, Science 310 (2005) 14921495.
[77] R. Jahn, T. Lang, T.C. Sudhof, Cell 112 (2003) 519533.
[78] J.L. Stow, A.P. Manderson, R.Z. Murray, Nature Reviews. Immunology 6 (2006)
919929.
[79] T. Raabe, M. Bukrinsky, R.A. Currie, Journal of Biological Chemistry 273 (1998)
974980.
[80] W. Shurety, A. Merino-Trigo, D. Brown, D.A. Hume, J.L. Stow, Journal of Interferon and Cytokine Research 20 (2000) 427438.
[81] J.K. Pagan, F.G. Wylie, S. Joseph, C. Widberg, N.J. Bryant, D.E. James, J.L. Stow, Current Biology 13 (2003) 156160.
[82] Z.Z. Lieu, J.G. Lock, L.A. Hammond, N.L. La Gruta, J.L. Stow, P.A. Gleeson, Proceedings of the National Academy of Sciences of the United States of America 105
(2008) 33513356.
[83] P.A. Gleeson, J.G. Lock, M.R. Luke, J.L. Stow, Trafc 5 (2004) 315326.
[84] J.E. Rothman, Nature Medicine 8 (2002) 10591062.
[85] R.Z. Murray, F.G. Wylie, T. Khromykh, D.A. Hume, J.L. Stow, Journal of Biological
Chemistry 280 (2005) 1047810483.
[86] P.C. Low, R. Misaki, K. Schroder, A.C. Stanley, M.J. Sweet, R.D. Teasdale, B.
Vanhaesebroeck, F.A. Meunier, T. Taguchi, J.L. Stow, The Journal of Cell Biology
190 (2010) 10531065.
[87] R.A. Black, C.T. Rauch, C.J. Kozlosky, J.J. Peschon, J.L. Slack, M.F. Wolfson, B.J.
Castner, K.L. Stocking, P. Reddy, S. Srinivasan, N. Nelson, N. Boiani, K.A.
Schooley, M. Gerhart, R. Davis, J.N. Fitzner, R.S. Johnson, R.J. Paxton, C.J. March,
D.P. Cerretti, Nature 385 (1997) 729733.
[88] K.A. Rozenova, G.M. Deevska, A.A. Karakashian, M.N. Nikolova-Karakashian,
Journal of Biological Chemistry 285 (2010) 2110321113.
[89] V. Cavalli, F. Vilbois, M. Corti, M.J. Marcote, K. Tamura, M. Karin, S. Arkinstall, J.
Gruenberg, Molecular Cell 7 (2001) 421432.
[90] M. Bhattacharya, N. Ojha, S. Solanki, C.K. Mukhopadhyay, R. Madan, N. Patel, G.
Krishnamurthy, S. Kumar, S.K. Basu, A. Mukhopadhyay, EMBO Journal 25
(2006) 28782888.
[91] A.E. Medvedev, I. Sabroe, J.D. Hasday, S.N. Vogel, Journal of Endotoxin Research
12 (2006) 133150.
[92] W. Ouyang, S. Rutz, N.K. Crellin, P.A. Valdez, S.G. Hymowitz, Annual Review of
Immunology 29 (2011) 71109.
[93] A. Sing, A. Roggenkamp, A.M. Geiger, J. Heesemann, Journal of Immunology 168
(2002) 13151321.
[94] H. Louis, O. Le Moine, M.O. Peny, E. Quertinmont, D. Fokan, M. Goldman, J.
Deviere, Hepatology 25 (1997) 13821389.
[95] H. Louis, O. Le Moine, M.O. Peny, B. Gulbis, F. Nisol, M. Goldman, J. Deviere, Gastroenterology 112 (1997) 935942.
[96] L. Williams, L. Bradley, A. Smith, B. Foxwell, Journal of Immunology 172 (2004)
567576.
[97] J.K. Riley, K. Takeda, S. Akira, R.D. Schreiber, Journal of Biological Chemistry 274
(1999) 1651316521.
[98] A. Matsukawa, S. Kudo, T. Maeda, K. Numata, H. Watanabe, K. Takeda, S. Akira, T.
Ito, Journal of Immunology 175 (2005) 33543359.
[99] A. Matsukawa, K. Takeda, S. Kudo, T. Maeda, M. Kagayama, S. Akira, Journal of
Immunology 171 (2003) 61986205.
[100] M. Kobayashi, M.N. Kweon, H. Kuwata, R.D. Schreiber, H. Kiyono, K. Takeda, S.
Akira, Journal of Clinical Investigation 111 (2003) 12971308.
[101] H. Yasukawa, M. Ohishi, H. Mori, M. Murakami, T. Chinen, D. Aki, T. Hanada, K.
Takeda, S. Akira, M. Hoshijima, T. Hirano, K.R. Chien, A. Yoshimura, Nature Immunology 4 (2003) 551556.
[102] J.G. Bode, A. Nimmesgern, J. Schmitz, F. Schaper, M. Schmitt, W. Frisch, D.
Hussinger, P.C. Heinrich, L. Graeve, FEBS Letters 463 (1999) 365370.
[103] C. Niemand, A. Nimmesgern, S. Haan, P. Fischer, F. Schaper, R. Rossaint, P.C.
Heinrich, G. Muller-Newen, Journal of Immunology 170 (2003) 32633272.

[104] A.H. Dalpke, S. Opper, S. Zimmermann, K. Heeg, Journal of Immunology 166

(2001) 70827089.
[105] J.G. Bode, J. Schweigart, J. Kehrmann, C. Ehlting, F. Schaper, P.C. Heinrich, D.
Hussinger, Journal of Immunology 171 (2003) 257266.
[106] X.P. Yang, U. Albrecht, V. Zakowski, R.M. Sobota, D. Hussinger, P.C. Heinrich, S.
Ludwig, J.G. Bode, F. Schaper, Journal of Biological Chemistry 279 (2004)
4527945289.
[107] C. Ehlting, W.S. Lai, F. Schaper, E.D. Brenndorfer, R.J. Matthes, P.C. Heinrich, S.
Ludwig, P.J. Blackshear, M. Gaestel, D. Hussinger, J.G. Bode, Journal of Immunology 178 (2007) 28132826.
[108] A. Yoshimura, T. Naka, M. Kubo, Nature Reviews. Immunology 7 (2007)
454465.
[109] P.C. Heinrich, I. Behrmann, S. Haan, H.M. Hermanns, G. Mller-Newen, F.
Schaper, Biochemical Journal 374 (2003) 120.
[110] R. Lang, A.L. Pauleau, E. Parganas, Y. Takahashi, J. Mages, J.N. Ihle, R. Rutschman,
P.J. Murray, Nature Immunology 4 (2003) 546550.
[111] V.S. Carl, J.K. Gautam, L.D. Comeau, M.F. Smith Jr., Journal of Leukocyte Biology
76 (2004) 735742.
[112] C.J. Greenhill, S. Rose-John, R. Lissilaa, W. Ferlin, M. Ernst, P.J. Hertzog, A.
Mansell, B.J. Jenkins, Journal of Immunology 186 (2011) 11991208.
[113] C. Ehlting, D. Hussinger, J.G. Bode, Biochemical Journal 387 (2005) 737745.
[114] C.J. Auernhammer, C. Bousquet, S. Melmed, Proceedings of the National Academy of Sciences of the United States of America 96 (1999) 69646969.
[115] J.G. Bode, S. Ludwig, C.A. Freitas, F. Schaper, M. Ruhl, S. Melmed, P.C. Heinrich, D.
Hussinger, Biological Chemistry 382 (2001) 14471453.
[116] H. Kiu, D.J. Hilton, N.A. Nicola, M. Ernst, R. Marquez, W.S. Alexander, A.W.
Roberts, E.J. McManus, Growth Factors 25 (2007) 319328.
[117] S. Radtke, S. Wuller, X.P. Yang, B.E. Lippok, B. Mutze, C. Mais, H.S. de Leur, J.G.
Bode, M. Gaestel, P.C. Heinrich, I. Behrmann, F. Schaper, H.M. Hermanns, Journal
of Cell Science 123 (2010) 947959.
[118] N. Hirose, T. Maekawa, T. Shinagawa, S. Ishii, Biochemical and Biophysical Research Communications 385 (2009) 7277.
[119] H. Qin, K.L. Roberts, S.A. Niyongere, Y. Cong, C.O. Elson, E.N. Benveniste, Journal
of Immunology 179 (2007) 59665976.
[120] R.A. Salmon, X. Guo, H.S. Teh, J.W. Schrader, European Journal of Immunology 31
(2001) 32183227.
[121] W. Ma, W. Lim, K. Gee, S. Aucoin, D. Nandan, M. Kozlowski, F. Diaz-Mitoma, A.
Kumar, Journal of Biological Chemistry 276 (2001) 1366413674.
[122] S. Sarkar, J. Han, K.S. Sinsimer, B. Liao, R.L. Foster, G. Brewer, S. Pestka, Molecular
and Cellular Biology 31 (2011) 602615.
[123] D. Avni, O. Ernst, A. Philosoph, T. Zor, Molecular Immunology 47 (2010)
13961403.
[124] J.X. Jiang, Y. Zhang, S.H. Ji, P. Zhu, Z.G. Wang, Shock 18 (2002) 336341.
[125] H. Chi, S.P. Barry, R.J. Roth, J.J. Wu, E.A. Jones, A.M. Bennett, R.A. Flavell, Proceedings of the National Academy of Sciences of the United States of America 103
(2006) 22742279.
[126] K.V. Salojin, I.B. Owusu, K.A. Millerchip, M. Potter, K.A. Platt, T. Oravecz, Journal
of Immunology 176 (2006) 18991907.
[127] Q. Zhao, X. Wang, L.D. Nelin, Y. Yao, R. Matta, M.E. Manson, R.S. Baliga, X. Meng,
C.V. Smith, J.A. Bauer, C.H. Chang, Y. Liu, The Journal of Experimental Medicine
203 (2006) 131140.
[128] M. Saraiva, J.R. Christensen, A.V. Tsytsykova, A.E. Goldfeld, S.C. Ley, D. Kioussis, A.
O'Garra, Journal of Immunology 175 (2005) 10411046.
[129] S.S. Iyer, A.A. Ghaffari, G. Cheng, Journal of Immunology 185 (2010) 65996607.
[130] G.D. Kalliolias, L.B. Ivashkiv, Journal of Immunology 180 (2008) 63256333.
[131] N. Ronkina, A. Kotlyarov, O. Dittrich-Breiholz, M. Kracht, E. Hitti, K. Milarski, R.
Askew, S. Marusic, L.L. Lin, M. Gaestel, J.B. Telliez, Molecular and Cellular Biology
27 (2007) 170181.
[132] S.K. Yang, Y.C. Wang, C.C. Chao, Y.J. Chuang, C.Y. Lan, B.S. Chen, BMC Medical
Genomics 3 (2010) 19.
[133] G. An, Mathematical Biosciences 217 (2009) 4352.
[134] G.C. An, J.R. Faeder, Mathematical Biosciences 217 (2009) 5363.
[135] M. Scheibel, B. Klein, H. Merkle, M. Schulz, R. Fritsch, F.R. Greten, M.C. Arkan, G.
Schneider, R.M. Schmid, The Journal of Experimental Medicine 207 (2010)
26212630.
[136] P. Rao, M.S. Hayden, M. Long, M.L. Scott, A.P. West, D. Zhang, A. Oeckinghaus, C.
Lynch, A. Hoffmann, D. Baltimore, S. Ghosh, Nature 466 (2010) 11151119.
[137] J.E. Thompson, R.J. Phillips, H. Erdjument-Bromage, P. Tempst, S. Ghosh, Cell 80
(1995) 573582.
[138] M.M. Spannbauer, C. Trautwein, Hepatology 49 (2009) 13871389.
[139] A. Hoffmann, A. Levchenko, M.L. Scott, D. Baltimore, Science 298 (2002)
12411245.