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Originally published online as doi:10.1189/jlb.0403194 on January 14, 2004

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(Journal of Leukocyte Biology. 2004;75:422-427.)
© 2004 by Society for Leukocyte Biology

Regulation of TLR signaling and inflammation by SOCS family proteins

Akihiko Yoshimura1, Hiroyuki Mori Masanobu Ohishi, Daisuke Aki and Toshikatsu Hanada

Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

1 Correspondence: Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: yakihiko{at}bioreg.kyushu-u.ac.jp


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ABSTRACT
 
Immune and inflammatory systems are controlled by multiple cytokines, including interleukins and interferons. These cytokines exert their biological functions through Janus tyrosine kinases and signal transducer and activator of transcription factors. The cytokine-inducible Src homology 2 protein (CIS) and suppressors of cytokine signaling (SOCS) are a family of intracellular proteins, several of which have emerged as key physiological regulators of cytokine responses, including those that regulate the inflammatory systems. In this short review, we focused on the molecular mechanism of the action of CIS/SOCS family proteins and their roles in Toll-like receptor signal regulation and inflammatory diseases.

Key Words: cytokine • tyrosine kinase • Toll-like receptor • STAT • NF-{kappa}B • inflammatory bowel disease • rheumatoid antithesis • endotoxin


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INTRODUCTION
 
Cytokines regulate many physiological responses and homeostasis; they influence the survival, proliferation, differentiation, and functional activity of cells of the immune system, as well as those of most other organ systems [1 ]. Cytokines, including interleukins (ILs), interferons (IFNs), and hemopoietins, activate the Janus tyrosine kinases (JAKs) JAK1, JAK2, and JAK3 and Tyk2, which associate with their cognate receptors. Activated JAKs phosphorylate the receptor cytoplasmic domains that create docking sites for Src homology 2 (SH2)-containing signaling proteins. Among the substrates of tyrosine phosphorylation are members of the signal transducers and activators of the transcription family of proteins (STATs) [2 , 3 ]. For example, IFN-{gamma} uses JAK1 and JAK2, which mainly activate STAT1, whereas IL-6 binding to the IL-6 receptor {alpha} chain and gp130 primarily activates JAK1 and STAT3. It is interesting that the anti-inflammatory cytokine IL-10 also activates STAT3. STAT4 and STAT6 are essential for T helper cell type 1 (Th1) and Th2 development, as these are activated by IL-12 and IL-4, respectively. STAT5 is activated by many cytokines including IL-2, IL-7, erythropoietin (EPO), and growth hormones (GHs).

The suppressors of cytokine signaling (SOCS) and cytokine-inducible SH2 protein (CIS) are a family of intracellular proteins, several of which have been shown to regulate the responses of immune cells to cytokines [4 5 6 ]. The discovery of the SOCS proteins appeared to have defined an important mechanism for the negative regulation of the cytokine-JAK-STAT pathway; however, recent studies using gene-disrupted [knockout (KO)] mice revealed unexpected, profound roles of SOCS proteins in many immunological processes. Thus, SOCS proteins provide a challenging, new concept for studies of immunity.


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CIS/SOCS FAMILY, STRUCTURE, AND ACTION MECHANISM
 
First, we shall briefly summarize the CIS/SOCS family, as detailed reviews are published elsewhere [4 5 6 ]. There are eight CIS/SOCS family proteins: CIS, SOCS1, SOCS2, SOCS3, SOCS4, SOCS5, SOCS6, SOCS7, each of which has a central SH2 domain, an amino-terminal domain of variable length and sequence, and a carboxy-terminal 40 amino acid module, known as the SOCS box [4 5 6 ]. SOCS1 was identified independently in three laboratories [7 8 9 ]. The best-characterized SOCS family members are CIS, SOCS1, SOCS2, and SOCS3, and they have been characterized in a classical, negative-feedback loop to inhibit cytokine signal transduction. CIS and SOCS2 bind to phosphorylated tyrosine residues on activated (phosphorylated) cytokine receptors (Fig. 1 ). Competition or steric hindrance for binding sites that are used to recruit and activate STATs (especially STAT5) has been proposed as the mechanism by which CIS and SOCS2 inhibit cytokine signaling [10 , 11 ]. CIS is induced by cytokines that activate STAT5 and bind to receptors that activate STAT5; i.e., EPO, IL-2, IL-3, prolactin, and GH [10 ]. The inhibitory activity of SOCS2 is not as strong as CIS in cultured cells, and strangely, very high SOCS2 levels somehow enhance GH-induced activation of STAT5 [12 13 14 ]. Nevertheless, from an analysis of KO mice, SOCS2 has been shown to be a relatively specific negative regulator of GH-STAT5 [15 ]. SOCS5 has been shown to inhibit IL-4 signaling by interacting with the IL-4 receptor and inhibiting JAK1 binding to the receptor [16 ].



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  		Figure 1. The molecular mechanism by which SOCS proteins negatively regulate cytokine signaling. Cytokine stimulation activates the JAK-STAT pathway, leading to the induction of CIS, SOCS1, and/or SOCS3. CIS, SOCS1, and SOCS3 appear to inhibit signaling by different mechanisms: SOCS1 binds to the JAKs and inhibits catalytic activity, SOCS3 binds to JAK-proximal sites on cytokine receptors and inhibits JAK activity, and CIS blocks the binding of STATs to cytokine receptors. SOCS1 and SOCS3 contain a kinase inhibitory region (KIR) for the suppression of JAK tyrosine kinase activity. P, phosphorylation; JAB, JAK-binding protein.

SOCS1 and SOCS3 can inhibit JAK tyrosine kinase activity, as they have the KIR in their N-terminal domain, which is proposed to function as a pseudosubstrate [17 ] (Fig. 1) . A three-dimensional model of the SOCS1/JAK2 complex has been predicted [18 ]. Although SOCS1 binds directly to the activation loop of JAKs through its SH2 domain, the SOCS3-SH2 domain binds the cytokine receptor (Fig. 1) . The SOCS3-SH2 domain has been shown to bind to Y757 of gp130, Y985 of the leptin receptor, and Y401 of the EPO receptor, some of which are the same binding sites for the SH2-containing tyrosine phosphatase 2 (SHP2) [19 20 21 22 23 ]. As SHP2 can promote gp130 signaling through the activation of mitogen-activated protein kinases, it is possible that SOCS3 might also suppress aspects of gp130 signaling by competing with SHP2 for receptor binding. Alternatively, SHP2 may also negatively regulate gp130 signaling by dephosphorylating JAKs. De Souza et al. [24] have mapped the phosphopeptide-binding preferences of the SH2 domain from SOCS3 using degenerate phosphopeptide libraries. They found that the consensus ligand-binding motif for SOCS3 was pY-(S/A/V/Y/F)-hydrophobic-(V/I/L)-hydrophobic-(H/V/I/Y). The sequence around Y759 of gp130 (-pYSTVVH-) almost completely matches this motif. Although SOCS3 binds with much higher affinity to a gp130 phosphopeptide around Y759 than to phosphopeptides derived from other receptors, such as leptin and EPO receptors, multiple SOCS3-binding sites are predicted to exist in these receptors, which may compensate for weaker binding to individual sites.

The function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with elongins B and C, cullins, Rbx-1, and E2 [25 , 26 ]. Thus, CIS/SOCS family proteins, as well as other SOCS box-containing molecules, probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions. Therefore, SOCS proteins seem to combine specific inhibition (i.e., kinase inhibition by KIR) and a generic mechanism of targeting interacting proteins for proteasomal degradation. The importance of the SOCS box was probed for its crucial role in the suppression of the oncogenic activity of translocated ets leukemia-JAK2 by SOCS1 [27 , 28 ] and from data studying mice that were genetically modified to lack only the SOCS box of SOCS1 [29 ]. However, the SOCS box is also shown to be important for the stabilization and/or degradation of the SOCS1 and SOCS3 proteins themselves [25 ]. Haan et al. [30] showed that interaction with elongin C stabilizes SOCS3 protein expression and that phosphorylation of the SOCS box tyrosine residues disrupts the complex and enhances proteasome-mediated degradation of SOCS3. The role of the SOCS box in the function of each of the SOCS proteins remains to be investigated.


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SOCS1 AND INFLAMMATORY DISEASE
 
Although SOCS1 KO mice are normal at birth, they exhibit stunted growth and die within 3 weeks of age with a syndrome characterized by severe lymphopenia, activation of peripheral T cells, fatty degeneration, necrosis of the liver, and macrophage infiltration of major organs (acute SOCS-/- disease) [31 , 32 ]. The neonatal defects exhibited by SOCS1-/- mice appear to occur primarily as a result of unbridled IFN-{gamma} signaling, as SOCS1-/- mice that also lack the IFN-{gamma} gene or the IFN-{gamma} receptor gene do not die neonatally [33 34 35 ]. Constitutive activation of STAT1 as well as constitutive expression of IFN-{gamma}-inducible genes were observed in SOCS1 KO mice. These data strongly suggest that the excess IFN-{gamma} is derived from the abnormally activated T cells in SOCS1-/- mice. However, although neonatal or early adult disease was avoided by removing IFN-{gamma}, additional loss of SOCS1 significantly shortened the lifespan of the mice [36 ]. The major causes of premature death were contributed by the development of polycystic kidneys, pneumonia, chronic skin ulcers, and chronic granulomas in the gut and various other organs (chronic SOCS-/- disease) [36 ]. Recently, we showed that lymphocyte-specific SOCS1-transgenic (Tg) mice on the SOCS1-/- background, as well as SOCS1-/-CD28-/- double-KO mice, exhibited systemic lupus erythematosus-like autoimmune diseases with high levels of autoantibodies [37 ]. Therefore SOCS1-/- disease is a complex syndrome consisting of acute and chronic inflammatory diseases and autoimmune-type diseases. The pathology in SOCS-/- mice raises a challenging and profound question of how this abnormality occurs and how such abnormalities develop acute and chronic SOCS1-/- diseases.

Part of this phenotype might be explained by abnormal signaling, not only by IFN-{gamma} but also by other inflammatory cytokines including IL-2 [38 , 39 ], IL-6 [40 ], IL-12 [41 ], and IL-15 [42 , 43 ]. SOCS1 might also regulate tumor necrosis factor {alpha} (TNF-{alpha}) [44 ], lipopolysaccharide (LPS) [45 , 46 ], inflammatory response system [47 ], and c-kit signaling [48 ], although the molecular mechanisms have not been clarified.


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SOCS1 AND MACROPHAGE/DENDRITIC CELL (DC) REGULATION
 
SOCS1 has been shown to play an important regulatory role in macrophages and DC. Bacterial LPS triggers innate-immune responses through the Toll-like receptor (TLR)4. Other bacterial pathogens including CpG-DNA activate TLR family receptors. Regulation of TLR signaling is a key step for inflammation, septic shock, and innate/adaptive immunity. SOCS1 and SOCS3 were found to be induced by LPS or CpG-DNA stimulation in macrophages [49 50 51 ]; SOCS1 has been implicated in the hyporesponsiveness to cytokines such as IFN-{gamma} after exposure of macrophages to LPS. Further, SOCS1-deficient mice are found to be more sensitive to LPS shock than wild-type littermates [45 , 46 ]. SOCS1-/- mice (predisease onset), SOCS1+/- mice, and IFN-{gamma}-/-SOCS1-/- mice, as well as STAT1-/-SOCS1-/- mice, have all been shown to be hyper-responsive to LPS and very sensitive to LPS-induced lethality [45 , 46 ]. Macrophages from these mice produced increased levels of the proinflammatory cytokines, such as TNF-{alpha} and IL-12, as well as nitric oxide, in response to LPS. It is important that LPS tolerance was severely impaired in SOCS1-/- mice and macrophages. Overexpression of SOCS1 in a macrophage cell line resulted in the suppression of LPS signaling, indicating that SOCS1 negatively regulates not only the JAK/STAT pathway but also the TLR-nuclear factor (NF)-{kappa}B pathway. However, although the molecular mechanism of the suppression of the NF-{kappa}B pathway by SOCS1 has not been clarified, the phenotype of SOCS1-deficient macrophages might provide new insights into the regulation of TLR signaling.

We recently reported that SOCS1-deficient DC are also hyper-responsive to IFN-{gamma} and IL-4 [37 ]. We generated mice in which SOCS1 expression was restored in T and B cells on a SOCS1-/- background (SOCS1-/-Tg mice). In these mice, DC were abnormally accumulated in the thymus and spleen and produced high levels of B cell activation factor (BAFF)/B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL), resulting in the aberrant expansion of B cells and autoreactive antibody production (Fig. 2 ). SOCS1-deficient DC efficiently stimulated B cell proliferation in vitro and autoantibody production in vivo. These results indicate that SOCS1 plays an essential role in normal DC functions and in the suppression of systemic autoimmunity that develops in SOCS1-/-Tg mice [37 ] (Figs. 2 and 3 ). Furthermore, we speculate that SOCS1-/- DC are important players in the onset of SOCS1-/- diseases, as SOCS1-deficient DC can activate proliferation not only of B but also of allogenic T cells [37 ] (Fig. 2) . We also observed that T cells produce higher amounts of Th1 cytokines, such as IFN-{gamma} and TNF-{alpha} in response to SOCS1-/- DC than to wild-type (WT) DC (T. Hanada and Jun Tsukada, unpublished data).



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  		Figure 2. SOCS1-deficient DC may disrupt central and peripheral tolerance. SOCS1-deficient DC are hyperactivated and efficiently stimulate B cell proliferation and autoantibody production as well as T cell proliferation and strong cytokine production. Ig, Immunoglobulin; TCR, T cell receptor.



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  		Figure 3. Current, simple model of the roles of STAT1, STAT3 and SOCS1, SOCS3 in macrophage and DC activation. SOCS1 suppresses STAT1 (and NF-{kappa}B by TLRs), and SOCS3 suppresses STAT3 activated by gp130-related cytokines. STAT1 activates macrophages (M{varphi}) and DC, and STAT3 suppresses them; thus, SOCS1 is a negative and SOCS3 is a positive regulator of antigen-presenting cells (APCs).


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SOCS3 AND TLR SIGNAL MODULATION
 
IL-6 is a proinflammatory cytokine that plays a progressive role in many inflammatory diseases including Crohn’s disease (CD) and rheumatoid arthritis (RA), and IL-10 is an immunoregulatory cytokine, which has potent anti-inflammatory activity. Although the transcription factor STAT3 is essential for the function of IL-6 and IL-10 [52 ], it is not clear how these two cytokines exhibit such opposite functions. Recently, we demonstrated that at least in macrophages, SOCS3 is a key regulator of the divergent action of these two cytokines. In macrophages lacking the SOCS3 gene or carrying a mutation of the SOCS3-binding site (Y759F) in gp130, not only IL-10 but also IL-6 suppressed LPS-induced TNF-{alpha} production [53 ]. SOCS3 protein was strongly induced by IL-6 and IL-10 in the presence of LPS but selectively inhibited IL-6 signaling as a result of SOCS3 binding the IL-6 receptor, gp130 (Y759), but not the IL-10 receptor [53 ]. These data indicate that SOCS3 selectively blocks IL-6 signaling, interfering with its ability to inhibit LPS signaling. Consistent with this, mice specifically lacking the SOCS3 gene in macrophages and neutrophils are resistant to acute inflammation as modeled by LPS shock. This phenotype is the complete opposite of macrophages in STAT3-conditional KO mice, which were more sensitive to LPS shock and produced more TNF-{alpha} in response to LPS [52 ]. A similar, opposite relationship between STAT3 and SOCS3 has been observed in DC. Recently, STAT3-deficient DC have been shown to be hyperactivated [54 ]. In contrast, we found that SOCS3-deficient DC possess less T cell activation potential than WT DC (Tomiko Matsumura et al., unpublished data). Thus, STAT3 prevents macrophage as well as DC activation, and SOCS3 suppresses this activity (Fig. 3) .

Others have shown that IL-6 strongly activates STAT1 and induces the expression of IFN-responsive genes in SOCS3-deficient macrophages, implying that IL-6 might mimic the action of IFNs [55 , 56 ]. These results appear to be contradictory to ours but can be supported by previous observations that IFNs have some immunosuppressive activities [57 ]. Thus, IL-6 may induce IFN-like anti-inflammatory action through the activation of STAT1 (and STAT3) in the absence of SOCS3. However, it has been difficult to determine the in vivo role of SOCS3, as the physiological effect of SOCS3 deficiency in macrophages was only examined in response to LPS. Nevertheless, all these studies agreed that SOCS3 deficiency results in the sustained activation of STAT3 in response to IL-6, which had not been observed in mice lacking SOCS1. All these studies indicate that SOCS3 is a specific, negative regulator for gp130-related cytokines in vivo.

The defects of SOCS3 expression and function in APCs and T cells may be related to certain immunological diseases. For example, a mouse line with a mutated gp130, to which SOCS3 cannot bind, developed a RA-like joint disease with increased production of Th1-type cytokines and Igs of the IgG2a and IgG2b classes [58 ]. Another group reported gastric adenoma in similar mutant mice [59 ]. Although it has not been investigated whether SOCS3 plays a major role in the development of these diseases, this possibility is worthy of examination.


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SOCS3 AND INFLAMMATORY DISEASES
 
In the preceding section, SOCS3 is described to function as a proinflammatory gene by suppressing IL-6/gp130 signaling in macrophages (see Fig. 3 ). However, in a pathological situation, there are accumulated evidences that SOCS3 could suppress inflammatory reaction in which IL-6-related cytokines play important, progressive roles. STAT3 activation and high SOCS3 expression levels have been found in epithelial and lamina propria cells in the colon of intestinal bowel disease model mice, as well as in human ulcerative colitis and CD patients [60 ] and in synovial fibroblasts of RA patients [61 ]. In a dextran-sulfate, sodium-induced, mouse colitis model, a time-course experiment indicated that STAT3 activation was 1 day ahead of SOCS3 induction; STAT3 activation became apparent during days 3–5 and decreased thereafter, and SOCS3 expression was induced at day 5 and maintained high levels thereafter. In murine models of inflammatory synovitis, STAT3 phosphorylation preceded SOCS3 expression, which is consistent with the idea that SOCS3 is part of a JAK/STAT negative-feedback loop [60 , 61 ]. The IL-6/STAT3 pathway promotes the progression of the chronic status of diseases by contributing to cytokine and growth factor production, tissue hyperplasia, synovial fibroblast proliferation, fibrosis, and osteoclast activation. Based on the evidence that forced expression of SOCS3 can inhibit IL-6-mediated STAT3 activation, we propose that SOCS3 is a negative regulator of inflammatory diseases, especially in those where IL-6 levels are very high.


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CONCLUSION
 
SOCS proteins are regulators of cytokine signal transduction and are essential for normal immune physiology but also appear to contribute to the development immunological disorders. Further understanding of the action of SOCS proteins in immunity, as well as their applications for therapeutics and drug discovery will depend on extending the studies of defining the physiological functions of each SOCS proteins and the relative interaction affinities of specific SOCS partner proteins in vivo. In general, SOCS1 suppresses STAT1, and SOCS3 suppresses STAT3. STAT1 activates macrophages and DC, and STAT3 suppresses them; thus, SOCS1 is a negative, and SOCS3 is a positive regulator of APCs (see Fig. 3 ). The molecular mechanism of APC regulation by STAT and SOCS, in addition to T cell regulation, is largely unknown and will be a new field of immune regulation by cytokines and their intracellular signaling pathways. The accumulated evidence regarding a balance of positive and negative pathways is important for understanding an overview of immune systems, and this recently acquired knowledge will provide new insights for the development of novel, therapeutic strategies for immunological diseases.


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ACKNOWLEDGEMENTS
 
We thank Y. Kawabata for technical assistance and N. Arifuku and F. Yamaura for preparation of the manuscript.

Received April 30, 2003; revised November 23, 2003; accepted November 24, 2003.


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