The Journal of Allergy and Clinical Immunology
Volume 119, Issue 3 , Pages 739-745, March 2007

Suppressor of cytokine signaling in allergic inflammation

  • Judit Knisz, MSc
    • ,
  • Paul B. Rothman, MD

      Affiliations

    • Corresponding Author InformationReprint requests: Paul B. Rothman, MD, Roy J. and Lucille A. Carver College of Medicine, Department of Internal Medicine, SE308 GH, 200 Hawkins Drive, Iowa City, IA 52242.

From the University of Iowa, Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine

Received 24 October 2006; received in revised form 8 December 2006; accepted 11 December 2006. published online 31 January 2007.

Iowa City, Iowa

Article Outline

The immunopathological hallmark of allergic diseases is elevated total and allergen specific serum IgE levels along with inflammation. This inflammation results from the activation of a cadre of hematopoietic and nonhematopoetic cells. This coordinated activation is the result of the increased production of a variety of soluble factors including chemokines and cytokines. The magnitude and the duration of cytokine action will determine the response to an allergen, either mounting a low-grade immunologic response or resulting in exaggerated reaction such as asthma or atopic dermatitis. Thus, the action of cytokines is tightly regulated both developmentally and within the cell. The suppressor of cytokine signaling (SOCS) protein family represents a novel group of cytoplasmic negative feedback regulators of type I and II cytokines. Several of the signaling pathways regulated by SOCS proteins are important in allergic immune responses. Thus, SOCS proteins may be important regulators of atopy.

Key words: Allergy, asthma, suppressor of cytokine signaling, SOCS, JAK/STAT

Abbreviations used: AD, Atopic dermatitis, CIS1, Cytokine-induced Src homology 2–containing protein, EGFR, Epidermal growth factor, EPO, Erythropoietin, ESS, Extended Src homology 2 subdomain, GH, Growth hormone, IRS, Insulin receptor substrate, KIR, Kinase inhibitory region, LIF, Leukemia inhibitory factor, MEF, Mouse embryonic fibroblast, SH, Src homology, SHP, Src homology 2 domain–containing tyrosine phosphatase, SOCS, Suppressor of cytokine signaling, STAT, Signal transducer and activator of transcription, TLR, Toll-like receptor

 

Inhalation of allergens in sensitized patients initiates a cascade of events that leads to the recruitment and activation of inflammatory cells (including eosinophils, lymphocytes, and macrophages). This allergic inflammatory state requires the production of an array of soluble mediators, the best characterized of which are cytokines. For example, the TH2 cytokines IL-4, IL-5, and IL-13 are important in the initiation and propagation of allergic inflammatory responses. IL-4 is important for the initiation of allergic immune responses through its role as the major inducer of the TH2 subset of T cells. IL-4 is also important for the production of IgE. IL-5 is essential for mounting a large eosinophil response. IL-13 regulates many of the effector responses that occur during allergic immune responses.

One of the essential properties of cytokines is their limited duration of action. This property leads to the effective curtailment of immune responses once the allergen is removed from the responding organ. Recent studies have demonstrated that cytokine signaling is limited by several mechanisms. In this review, we summarize our current understanding of the regulation of cytokine signaling in allergic states and focus the discussion on a family of proteins, suppressors of cytokine signaling (SOCSs), which are important modulators of cytokine function in vivo.

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Regulating cytokine signaling 

Signaling cascades initiated by most type I and type II cytokines appear to follow a similar paradigm (Fig 1). Signaling downstream of the cytokine IL-4 serves as an example of this model. IL-4 induces activation, proliferation, and differentiation of a variety of hematopoietic cells, including B cells, T cells, and mast cells.1 In hematopoietic cells, the IL-4 receptor is heterodimeric, composed of 1 ligand-specific α chain (IL-4Rα) and either 1 common γ chain (γC) or the IL-13Rα chain (see review2). Two nonreceptor tyrosine kinases, Janus kinase (JAK)1 and JAK3, constitutively associate with the IL-4 receptor chains (JAK1 with IL-4Rα and JAK3 with γC or IL-13Rα chain). When the IL-4 receptor binds its ligand, it oligomerizes, and JAK1 and JAK3 become activated. The JAK1 kinase then phosphorylates tyrosines present within the cytoplasmic domain of the IL-4Rα chain. These phosphorylated tyrosines are docking sites for the phosphotyrosine binding domain or Src homology (SH)–2 domain of specific signaling molecules. One such IL-4 signaling molecule is signal transducer and activator of transcription (STAT)–6, a member of the STAT family of transcription factors (see review2). STAT6 is phosphorylated, and thereby activated, by JAK kinases. Phosphorylated STAT6 activates transcription of genes involved in B-cell and T-cell differentiation. The induction of GATA3 by STAT6 leads to the production of TH2 cells. The ability of B cells to perform immunoglobulin heavy chain class-switching to IgE requires that STAT6 activates the Iɛ promoter.

  • View full-size image.
  • Fig 1. 

    SOCS-1 in cytokine signaling. On IL-4 or IL-13 binding to the receptor complex, STAT6 becomes phosphorylated and translocates to the nucleus as a homodimer. In the nucleus, STAT6 dimer activates the transcription of cytokine responsive genes such as IgE and CD23. During IL-4 signaling, the protein level of SOCS1 is elevated and negatively regulates cytokine signaling. SOCS1 was shown to downregulate cytokine signaling by 2 distinct mechanisms: (1) SOCS1 can directly bind to and inactivate tyrosine kinases, including all 4 JAK kinases; and (2) SOCS1 functions as a component of E3 ubiquitin ligase complex that regulates the ubiquitination and subsequent proteasomal degradation of target substrates such as JAK kinases. Ub, Ubiquitin; Cytokine RE, cytokine response element.

The magnitude and duration of cytokine action are limited by a variety of mechanisms. The developmental regulation of cytokine receptor expression is an important mechanism used by the immune system to limit biologic effects of cytokines.3, 4 Within the cell, cytokine signaling is regulated within the membrane, cytoplasm, and nucleus. Tyrosine phosphorylation regulates various components of the signaling pathway, and the tyrosine phosphatases (eg, Src homology 2 domain–containing tyrosine phosphatase [SHP]–1 and CD45) can bind to activated cytokine receptor complexes to limit the duration and/or magnitude of cytokine signaling.5, 6, 7 The activated STAT molecules can be regulated in the cytoplasm (by proteasomal degradation, interaction with protein inhibitor of activated STAT, or covalent linkage to the ISG15 protein8) and in the nucleus (by phosphatases such as T-cell protein tyrosine phosphatase9 or E3 ligases such as STAT-interacting LIM protein10). In addition to these, the SOCS family of proteins is a major regulator of signaling in cells.

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SOCS family 

The SOCS protein family consists of 8 members: cytokine-induced SH2-containing protein (CIS1) and SOCS1 through 7. The family is defined by predicated common structural motifs including a central SH2 domain and a SOCS box motif in the carboxyl terminus (Fig 2). The SOCS box shares homology with the F box, a motif for ubiquitin-dependent proteolysis, and is present in proteins such as S-phase kinase–associated protein (Skp1).11 A SOCS box has been identified in more than 40 proteins, including the von Hippel-Lindau tumor suppressor protein. The structure of SOCS box is conserved among SOCS family members and can interact with the elonginB/C complex, a component of an E3 ligase.12

The structurally related SOCS proteins negatively regulate cytokine signaling by at least 3 distinct mechanisms (Fig 1). First, SOCS proteins can directly bind to and inactivate tyrosine kinases, including all 4 JAK kinases, insulin receptor, and Tec kinases.13, 14, 15, 16, 17 Second, SOCS proteins bind to cytokine receptors and can occupy docking sites otherwise available for signal transduction mediators such as STATs and SHP2.18 Third, SOCS proteins function as components of E3 ligases that regulate the ubiquitination and subsequent proteasomal degradation of target substrates such as JAK kinases19, 20 and Vav.21 X-ray crystallography of murine SOCS2 and SOCS3 reveals structures that are consistent with these data.22, 23 SOCS2 was crystallized in complex with elonginB and elonginC, supporting the idea that SOCS proteins function as E3 ubiquitin ligases. The 3-dimensional structure of SOCS2 shows 3 conserved SOCS family domains: an N-terminal extended SH2 domain, a central SH2 domain with a classic phosphotyrosine pocket, and a C-terminal SOCS box. Through their SH2 domain, SOCS proteins recognize and bind phosphorylated proteins such as JAKs or cytokine receptors. This binding can block other signaling molecules from binding or being targeted for proteasomal degradation. The SOCS2 crystal structure defined the phosphotyrosine binding region—the pY pocket. The pY pocket is conserved among other SOCS family members. In SOCS2, the pY pocket (amino acids R73-D74-S75) binds to pY595 of growth hormone receptor, the binding site of the SHP2 phosphatase, and STAT5b. This provides 1 potential mechanism for SOCS2-dependent suppression.23

Although SOCS proteins share significant similarity in their SOCS box and SH2 domain, they vary in the length and the structure of their N-terminus. CIS1 and SOCS1 to SOCS3 SH2 domains have a similar α-helical N-terminal extension, the extended SH2 subdomain (ESS). The SOCS1 and SOCS3 ESS is structurally linked to the protein's functionally important kinase inhibitory region (KIR). Only SOCS1 and SOCS3 possess a KIR domain, which resembles the activation loop of JAKs and can mimic the activation loop by functioning as a pseudosubstrate.24 SOCS7 is unique in that it has 4 polyproline regions in its N-terminus that may allow association with SH3 domain–containing proteins such as Vinexin and Nck.25, 26

Recently it was shown that another E3 ubiquitin ligase, Haem oxidized IRP2 ubiquitin ligase-1, can interact with SOCS6, thereby sending SOCS6-containing complexes to the proteasome.27 This requires that HOIL-1's ubiquitin-like domain simultaneously bind the SOCS box and the SH2 domain. Paradoxically, when HOIL-1 associates with SOCS6, it not only induces ubiquitination of SOCS6-containing complexes but also can delay SOCS6 protein degradation. As yet, however, the mechanism allowing HOIL-1 to stabilize SOCS6 remains unclear.

To date, most studies have focused on the actions of CIS1, SOCS1, and SOCS3, whereas little is known about the function of the other SOCS proteins. Yet predictions can be inferred by sequence homology. Mammalian SOCS genes exhibit similarities in sequence and function, suggesting underlying redundancy. It is interesting that the strongest protein identities are found in pairwise clusters between SOCS1/SOCS3, CIS1/SOCS2, SOCS4/SOCS5, and SOCS6/SOCS7. This likely reflects similarity at the functional level as well.

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SOCS1 

Suppressor of cytokine signaling 1, the best studied of the family, was cloned by 3 separate methods by different investigators15, 17, 28: one group identified SOCS1 in a screen for inhibitors of IL-6 signaling, another group identified the protein in a screen for JAK binding proteins, and the third group identified SOCS1 while cloning genes encoding proteins with “STAT-like” SH2 domains. In vitro, interaction between SOCS1 and JAK kinases inhibits JAK tyrosine kinase activity.15, 17 This interaction localizes to the SOCS1 SH2 domain and inhibits all 4 JAK kinases. Hypothetically, this should disrupt cytokine signaling in vivo.

Multiple studies have demonstrated that overexpression of SOCS1 can inhibit signaling downstream of multiple cytokines that use JAK kinases for their intracellular signaling, including IFN-α, IFN-γ, IL-2, IL-3, IL-4, IL-6, growth hormone (GH), prolactin, erythropoietin (EPO), oncostatin M, thymic stromal lymphopoietin, thrombopoietin, and leukemia inhibitory factor (LIF). Analyses of cells from Socs-1–deficient mice have suggested increased and/or prolonged signaling downstream of some of these cytokines.

Socs1−/− mice, although normal at birth, quickly develop a number of abnormalities. They are stunted and contract a multiorgan disease characterized by lymphopenia, fatty acid degeneration of the liver, and macrophages infiltrating various tissues. Socs1−/− mice die before 3 weeks of age. Lethality however, can be significantly delayed in the Rag2−/−, Ifn-γ−/−, Stat1−/−, and Stat6−/− backgrounds, implying that SOCS1 is a critical regulator of IFN-γ and IL-4 signaling. Both IL-4 and IFN-γ can induce SOCS1 protein level in bone marrow. These data suggest a model in which SOCS1 can act in an autofeedback loop to regulate IL-4 or IFN-γ signaling. Indeed, naive Socs1+/−CD4+ T cells have increased potential to differentiate in vitro into either TH1 or TH2 cells. Similarly, in vivo Socs1+/−CD4+ T cells produced more IFN-γ than Socs1+/+ cells after infection with Listeria monocytogenes. Also, Socs1+/−CD4+ T cells produced more IL-4 when inoculated with Nippostrongylus braziliensis, a TH2-inducing parasite.29 Thus, SOCS1 is critical for regulating cytokines that balance TH1 and TH2 development, making it an attractive gene for studies concerning allergic diseases.

It was recently suggested that SOCS1 also regulates Toll-like receptor (TLR) signaling. On TLR stimulation, SOCS1 targets MyD88-adapter-like, the TLR-2 and TLR-4 adaptor, to the 26S proteasome.30 Indeed, Socs1−/− macrophages are hypersensitive to LPS, and Ifn-γ−/−Socs1−/− mice were sensitive to LPS-induced lethality.31 TLRs were shown to be important in controlling sensitization. Because mast cells express TLR4 on their surface, LPS-induced TLR4 signaling may modulate mast cells and influence allergic airway inflammation in vivo.32 Genetic association studies found correlations between asthma and atopy, and single nucleotide polymorphisms in some TLR family members, including TLR2 and TLR4 (see review33).

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CIS1 and SOCS2 

CIS1, the first Socs gene identified, is induced by cytokines such as EPO and IL-3, and associates with their tyrosine-phosphorylated receptors.34 CIS1 may be an adaptor protein that suppresses signaling either by recruiting a negative regulator or by occluding the phosphotyrosines that bind STAT5. The latter possibility is suggested by the binding similarities between the CIS and STAT5 SH2 domains. Transgenic mice overexpressing Cis1 are strikingly similar to Stat5 knockout mice, displaying growth retardation, defects in mammary gland development, and severe defects in natural killer cell, natural killer T cell, and T-cell development; in addition, their helper T cells are biased toward TH2 differentiation.35 Paradoxically, Cis1−/− mice are normal,36 making its role in the immune system unclear.

Suppressor of cytokine signaling 2 shares 35% amino acid identity with CIS1, and interacts with insulinlike growth factor 1 and GH, suggesting that it regulates signaling downstream of these growth factors. Interestingly, Socs2-deficient mice develop gigantism, supporting the importance of SOCS2 in the regulation of growth.37 However, transgenic Socs2 mice also have gigantism,38 illustrating that the role of SOCS2 in vivo is complex.

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SOCS3 

The SH2 domains of SOCS3 and SOCS1 share 40% homology. Multiple studies have demonstrated the capacity of both of these proteins to inhibit JAK/STAT signaling downstream of multiple cytokines. However, the mechanisms by which they alter signaling appear to differ. Whereas SOCS1 directly binds to and inhibits activated JAK kinases, SOCS3 inhibits JAK kinases when SOCS3 is bound to phosphorylated cytokine receptors.39 Deletion of SOCS3 results in uncontrolled LIF signaling, causing a placental defect and in turn neonatal lethality.40 This suggests a nonredundant role for SOCS3 in LIF signaling. However, SOCS3 is not restricted to LIF signaling regulation; SOCS3 is induced by various inflammatory and anti-inflammatory cytokines, such as IFN-γ, IL-3, IL-10, and granulocyte colony-stimulating factor. SOCS3 mRNA levels are upregulated after IL-6 stimulation in both naive CD4+ T cells and CD4+CD25high TREG cells.41

The role of SOCS3 in the regulation of cytokines in allergic responses is complex. Initially, SOCS3 was shown to inhibit IL-4–dependent STAT6 activation in 293T cells. However, B-cell lines that stably express SOCS3 do not display any alteration in IL-4 signaling.42 In mice, increased SOCS3 expression correlates with the pathology of allergic immune diseases. Decreased TH2 differentiation occurs in Socs3+/− mice and in cells overexpressing a dominant-negative form of SOCS3.43 A study of mice overexpressing SOCS3 in T cells revealed that SOCS3 does not regulate IL-4, but rather IL-12–mediated STAT4 signaling. Specifically, SOCS3 binds to the IL-12Rβ2 chain and inhibits STAT4 phosphorylation.43 These data suggest that SOCS3 regulates TH1 and TH2 differentiation. However, studies of T cells lacking SOCS3 have demonstrated a more complicated role for SOCS3. Yasukawa et al44 generated mice bearing loxP-flanked conditional alleles of Socs3 (Socs3fl/fl). Cross of Socs3fl/fl mice with mice expressing Cre recombinase under the control of mouse mammary tumor virus-long terminal repeat (CreMMTV) results in the deletion of SOCS3 in mammary gland, skin, B, and T cells. T cells from these mice demonstrate prolonged STAT3 phosphorylation and elevated IL-17 production. In fact, naive T cells lacking SOCS3 demonstrate increased differentiation into TH17 cells, even under TH1-biased conditions.45 This indicates a novel role for SOCS3 in TH cell differentiation, limiting the development of TH17 cell polarization. TH17 cells produce IL-17, hence the nomenclature, and IL-17 has been intensively studied recently. IL-17 is elevated in serum from patients with asthma, and there is evidence that IL-17 may recruit macrophages46 and neutrophils into the lung, exacerbating asthma (see review47).

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SOCS4 and SOCS5 

Suppressor of cytokine signaling 4 and SOCS5 were identified by searching the database for genes with SOCS box domains.48 SOCS4 is the least studied SOCS family member. SOCS4 levels are upregulated on EGF stimulation. In addition, SOCS4 and SOCS5 are the only SOCS family members that markedly reduce EGFR level.49 Little more is known about SOCS4 function in cytokine signaling. More data are available about the function of SOCS5; however, its in vivo function is not entirely clear. In TH1 cells, SOCS5 can bind to the IL-4R and suppress STAT6 phosphorylation. Furthermore, SOCS5 protein is selectively expressed in TH1 cells, and Socs5 transgenic mice have disrupted TH2-cell responses and attenuated IL-4 signaling.50 Socs5−/− mice, however, have normal CD4+ T-cell polarization.51

The Drosophila genome sequence revealed 3 Socs genes, one homologous to Socs4 and 5, the others to Socs6 and 7. Drosophila has a single cytokine receptor along with 1 homolog of JAK and 1 homolog of STAT. The pathway that employs these molecules appears to be important not only for larval hematopoiesis but also for sexual identity, embryo segmentation, and polarity in the eye (see review52). These results suggest that SOCS4 and 5 may have evolutionary importance that is not yet discerned.

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SOCS6 and SOCS7 

Suppressor of cytokine signaling 6 and SOCS7 are the most closely related SOCS proteins, sharing 56% amino acid identity in their SH2 domain and 53% in their SOCS box. In vitro, SOCS6 interacts with the insulin receptor, insulin receptor substrate (IRS)–4,16 and inhibits IRS-1 phosphorylation.16, 53 SOCS6 regulates the p85 subunit of the phosphoinositol-3 (PI3) kinase (p85PI3K), and overexpressed SOCS6 can inhibit insulin signaling,16 resulting in a phenotype similar to that of p85PI3K heterozygous mice. Although Socs6 transgenic mice display improved glucose and insulin tolerance, SOCS6−/− mice do not appear to be more insulin-responsive than wild-type mice. In fact, SOCS6 deletion reduces weight by 8% to 10%, but the mice seem otherwise normal.53 Thus, in vivo SOCS6's function is undefined.

Socs7−/− mice similarly show mild growth retardation. In addition, however, in the C57Bl/6 genetic background, about 50% of the mice develop hydrocephalus and suffer neonatal death.54 SOCS7 can interact with STAT3 and STAT5 after prolactin or leptin-induced stimulation.55 SOCS7 mRNA levels are induced on insulin stimulation. In vitro, SOCS7 interacts with the insulin receptor and IRS-1.56 IRS proteins are adaptor proteins that are essential mediators of insulin action. They can also be activated by various other ligands, such as cytokines, including interleukins (IL-2, IL-4, IL-9, IL-13), IFNs (IFN-α, IFN-β, and IFN-γ), and GH, thus performing important roles as regulators of lymphocyte proliferation and function.2 IRS proteins can also be phosphorylated by JAK kinases.

Coexpression of SOCS7 with IRS-1 in 293T cells causes decreased IRS-1 protein level, whereas the inhibition of the proteasome results in accumulation of ubiquitinated IRS-1. These data suggest that SOCS7 can target IRS-1 to ubiquitination and proteasome-mediated degradation. In concert with this, insulin stimulation of mouse embryonic fibroblasts (MEFs) causes reduction of IRS-1 protein level, whereas this reduction is not observed in Socs7-deficient MEF cells. In vivo, the loss of SOCS7 results in enlarged islet of Langerhans of the pancreas. These mice are born with normal islet mass but develop islet hyperplasia with age. SOCS7 KO mice are hypersensitive to insulin, and Socs7−/− MEFs show increased adipogenesis in response to stimulation with insulin, suggesting an essential, nonredundant role for SOCS7 in the regulation of insulin signaling in vivo.56

Some Socs7−/− mice develop a syndrome which, in some ways, resembles atopic dermatitis (AD). This phenotype is characterized by hair and whisker loss, skin thickening, and excoriation in regions accessible to the mice, presumably secondary to pruritus. Histological analysis revealed that compared with wild-type litter mates, Socs7−/− epidermis has an increased number of mast cells and an increased number of degranulated mast cells. Healthy Socs7−/− mice display the same phenomenon, suggesting that SOCS7 performs a role in the regulation of mast cells. Interestingly, mice that lack both Socs6 and Socs7 (Socs6/7 double knockout mice) develop an even more severe skin disease (J. Knisz, Q. Wu, L. McKeag, A. Banks, and P. B. Rothman, unpublished data, March 2006). Although the deletion of Socs6 alone has no demonstrable skin phenotype and no effect on any studied cytokine pathways, the deletion of both Socs6 and Socs7 results in severe phenotypes. This suggests an underlying redundancy between SOCS6 and SOCS7 that needs to be defined further.

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Clinical implications 

Disruption of negative feedback of the JAK/STAT pathway has been implicated in hematopoietic disorders, autoimmune diseases, and inflammatory diseases.57, 58 Study of the Socs gene targeted mice revealed important roles for SOCS proteins in the regulation of cytokine signaling (summarized in Table I) and their possible involvement in immune diseases. SOCS1 and SOCS3 have gained much attention in the field of allergy, mainly because of their involvement in the regulation of cytokines that balance TH1/TH2 development. Biopsies from patients with psoriasis or allergic contact dermatitis showed high levels of SOCS1, SOCS2, and SOCS3.59 A single nucleotide polymorphism in SOCS1 is associated with lower IgE levels in patients with asthma (J. Mostecki, D. Vercelli, F. Martinez, and P. Rothman, unpublished data, February 2006). A cDNA microarray study suggested that SOCS3 is associated with AD, and immunohistological analysis showed increased SOCS3 protein levels in dendritic cells and an increased number of SOCS3-positive cells in epidermis from AD skin. Genetic analysis of patients with AD suggests that specific haplotypes of the Socs3 gene may be associated with this disease.60 In addition, a positive correlation has been evident between SOCS3 and asthma pathology, as well as serum IgE levels in patents with allergy.43 These findings suggest important roles for SOCS1 and SOCS3 in regulating asthma and allergy and might serve as targets for therapeutic interventions in the treatment of allergic diseases.

Table I. Major phenotype of Socs gene deficiency
GeneMain pathway regulatedKOKO phenotype
CISEPO, IL-3√No abnormalities
SOCS1IFN-γ√Neonatal lethality caused by dysregulated IFN-γ signaling
SOCS2Insulinlike growth factor 1R, GH√Gigantism caused by dysregulated GH signaling
SOCS3IL-6√Embryonic lethality caused by dysregulated LIF signaling
SOCS4UnknownND—
SOCS5EGF√No abnormalities
SOCS6Unknown√Mild growth retardation
SOCS7Insulin√Hyperinsulinemia

ND, Not done.

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Conclusion 

The study of mice lacking genes encoding SOCS proteins has demonstrated the important role that these proteins perform in regulating the activity of an array of cytokines. Further, in many cases, mice lacking only 1 Socs gene demonstrate significant phenotypes, suggesting that, despite the predicted structural similarity of these proteins, they perform nonredundant functions in vivo. This likely results from the tissue-specific and developmental regulation of Socs gene expression. In addition, differences in the SH2 domains of different SOCS proteins likely impart distinct substrate specificities to these proteins. However, the generation of mice lacking more than 1 Socs gene also suggests some redundant functionality in vivo.

Many of the pathways regulated by SOCS proteins are important for the initiation of propagation of allergic immune responses. New data suggest that variants of Socs genes are present in human beings and that subtle alteration in the levels or structure of SOCS proteins may affect their function. The future may provide greater information regarding the importance of such variants in the predisposition to developing allergic diseases.

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References 

  1. Nelms K, Keegan AD, Zamorano J, Ryan JJ, Paul WE. The IL-4 receptor: signaling mechanisms and biologic functions. Annu Rev Immunol. 1999;17:701–738
  2. Jiang H, Harris MB, Rothman P. IL-4/IL-13 signaling beyond JAK/STAT. J Allergy Clin Immunol. 2000;105:1063–1070
  3. Pernis A, Gupta S, Gollob KJ, Garfein E, Coffman RL, Schindler C, et al. Lack of interferon gamma receptor beta chain and the prevention of interferon gamma signaling in TH1 cells. Science. 1995;269:245–247
  4. Bach EA, Szabo SJ, Dighe AS, Ashkenazi A, Aguet M, Murphy KM, et al. Ligand-induced autoregulation of IFN-gamma receptor beta chain expression in T helper cell subsets. Science. 1995;270:1215–1218
  5. David M, Grimley PM, Finbloom DS, Larner AC. A nuclear tyrosine phosphatase downregulates interferon-induced gene expression. Mol Cell Biol. 1993;13:7515–7521
  6. Neel BG. Role of phosphatases in lymphocyte activation. Curr Opin Immunol. 1997;9:405–420
  7. Neel BG, Tonks NK. Protein tyrosine phosphatases in signal transduction. Curr Opin Cell Biol. 1997;9:193–204
  8. Malakhova OA, Yan M, Malakhov MP, Yuan Y, Ritchie KJ, Kim KI, et al. Protein ISGylation modulates the JAK-STAT signaling pathway. Genes Dev. 2003;17:455–460
  9. ten Hoeve J, de Jesus Ibarra-Sanchez M, Fu Y, Zhu W, Tremblay M, David M, et al. Identification of a nuclear Stat1 protein tyrosine phosphatase. Mol Cell Biol. 2002;22:5662–5668
  10. Tanaka T, Soriano MA, Grusby MJ. SLIM is a nuclear ubiquitin E3 ligase that negatively regulates STAT signaling. Immunity. 2005;22:729–736
  11. Bai C, Sen P, Hofmann K, Ma L, Goebl M, Harper JW, et al. SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box. Cell. 1996;86:263–274
  12. Kamura T, Sato S, Haque D, Liu L, Kaelin WG, Conaway RC, et al. The Elongin BC complex interacts with the conserved SOCS-box motif present in members of the SOCS, ras, WD-40 repeat, and ankyrin repeat families. Genes Dev. 1998;12:3872–3881
  13. Dey BR, Furlanetto RW, Nissley P. Suppressor of cytokine signaling (SOCS)-3 protein interacts with the insulin-like growth factor-I receptor. Biochem Biophys Res Commun. 2000;278:38–43
  14. Dey BR, Spence SL, Nissley P, Furlanetto RW. Interaction of human suppressor of cytokine signaling (SOCS)-2 with the insulin-like growth factor-I receptor. J Biol Chem. 1998;273:24095–24101
  15. Endo TA, Masuhara M, Yokouchi M, Suzuki R, Sakamoto H, Mitsui K, et al. A new protein containing an SH2 domain that inhibits JAK kinases. Nature. 1997;387:921–924
  16. Mooney RA, Senn J, Cameron S, Inamdar N, Boivin LM, Shang Y, et al. Suppressors of cytokine signaling-1 and -6 associate with and inhibit the insulin receptor: a potential mechanism for cytokine-mediated insulin resistance. J Biol Chem. 2001;276:25889–25893
  17. Naka T, Narazaki M, Hirata M, Matsumoto T, Minamoto S, Aono A, et al. Structure and function of a new STAT-induced STAT inhibitor. Nature. 1997;387:924–929
  18. Ram PA, Waxman DJ. SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling by multiple mechanisms. J Biol Chem. 1999;274:35553–35561
  19. Monni R, Santos SC, Mauchauffe M, Berger R, Ghysdael J, Gouilleux F, et al. The TEL-Jak2 oncoprotein induces Socs1 expression and altered cytokine response in Ba/F3 cells. Oncogene. 2001;20:849–858
  20. Frantsve J, Schwaller J, Sternberg DW, Kutok J, Gilliland DG. Socs-1 inhibits TEL-JAK2-mediated transformation of hematopoietic cells through inhibition of JAK2 kinase activity and induction of proteasome-mediated degradation. Mol Cell Biol. 2001;21:3547–3557
  21. De Sepulveda P, Ilangumaran S, Rottapel R. Suppressor of cytokine signaling-1 inhibits VAV function through protein degradation. J Biol Chem. 2000;275:14005–14008
  22. Bergamin E, Wu J, Hubbard SR. Structural basis for phosphotyrosine recognition by suppressor of cytokine signaling-3. Structure. 2006;14:1285–1292
  23. Bullock AN, Debreczeni JE, Edwards AM, Sundstrom M, Knapp S. Crystal structure of the SOCS2-elongin C-elongin B complex defines a prototypical SOCS box ubiquitin ligase. Proc Natl Acad Sci U S A. 2006;103:7637–7642
  24. Yasukawa H, Misawa H, Sakamoto H, Masuhara M, Sasaki A, Wakioka T, et al. The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop. EMBO J. 1999;18:1309–1320
  25. Martens N, Wery M, Wang P, Braet F, Gertler A, Hooghe R, et al. The suppressor of cytokine signaling (SOCS)-7 interacts with the actin cytoskeleton through vinexin. Exp Cell Res. 2004;298:239–248
  26. Matuoka K, Miki H, Takahashi K, Takenawa T. A novel ligand for an SH3 domain of the adaptor protein Nck bears an SH2 domain and nuclear signaling motifs. Biochem Biophys Res Commun. 1997;239:488–492
  27. Bayle J, Lopez S, Iwai K, Dubreuil P, De Sepulveda P. The E3 ubiquitin ligase HOIL-1 induces the polyubiquitination and degradation of SOCS6 associated proteins. FEBS Lett. 2006;580:2609–2614
  28. Starr R, Willson TA, Viney EM, Murray LJ, Rayner JR, Jenkins BJ, et al. A family of cytokine-inducible inhibitors of signalling. Nature. 1997;387:917–921
  29. Fujimoto M, Tsutsui H, Yumikura-Futatsugi S, Ueda H, Xingshou O, Abe T, et al. A regulatory role for suppressor of cytokine signaling-1 in T(h) polarization in vivo. Int Immunol. 2002;14:1343–1350
  30. Mansell A, Smith R, Doyle SL, Gray P, Fenner JE, Crack PJ, et al. Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation. Nat Immunol. 2006;7:148–155
  31. Nakagawa R, Naka T, Tsutsui H, Fujimoto M, Kimura A, Abe T, et al. SOCS-1 participates in negative regulation of LPS responses. Immunity. 2002;17:677–687
  32. Nigo YI, Yamashita M, Hirahara K, Shinnakasu R, Inami M, Kimura M, et al. Regulation of allergic airway inflammation through Toll-like receptor 4-mediated modification of mast cell function. Proc Natl Acad Sci U S A. 2006;103:2286–2291
  33. Yang IA, Fong KM, Holgate ST, Holloway JW. The role of Toll-like receptors and related receptors of the innate immune system in asthma. Curr Opin Allergy Clin Immunol. 2006;6:23–28
  34. Yoshimura A, Ohkubo T, Kiguchi T, Jenkins NA, Gilbert DJ, Copeland NG, et al. A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors. EMBO J. 1995;14:2816–2826
  35. Matsumoto A, Seki Y, Kubo M, Ohtsuka S, Suzuki A, Hayashi I, et al. Suppression of STAT5 functions in liver, mammary glands, and T cells in cytokine-inducible SH2-containing protein 1 transgenic mice. Mol Cell Biol. 1999;19:6396–6407
  36. Marine JC, McKay C, Wang D, Topham DJ, Parganas E, Nakajima H, et al. SOCS3 is essential in the regulation of fetal liver erythropoiesis. Cell. 1999;98:617–627
  37. Greenhalgh CJ, Rico-Bautista E, Lorentzon M, Thaus AL, Morgan PO, Willson TA, et al. SOCS2 negatively regulates growth hormone action in vitro and in vivo. J Clin Invest. 2005;115:397–406
  38. Greenhalgh CJ, Metcalf D, Thaus AL, Corbin JE, Uren R, Morgan PO, et al. Biological evidence that SOCS-2 can act either as an enhancer or suppressor of growth hormone signaling. J Biol Chem. 2002;277:40181–40184
  39. Nicholson SE, De Souza D, Fabri LJ, Corbin J, Willson TA, Zhang JG, et al. Suppressor of cytokine signaling-3 preferentially binds to the SHP-2-binding site on the shared cytokine receptor subunit gp130. Proc Natl Acad Sci U S A. 2000;97:6493–6498
  40. Takahashi Y, Carpino N, Cross JC, Torres M, Parganas E, Ihle JN. SOCS3: an essential regulator of LIF receptor signaling in trophoblast giant cell differentiation. EMBO J. 2003;22:372–384
  41. Oberg HH, Wesch D, Grussel S, Rose-John S, Kabelitz D. Differential expression of CD126 and CD130 mediates different STAT-3 phosphorylation in CD4+CD25- and CD25high regulatory T cells. Int Immunol. 2006;18:555–563
  42. Losman JA, Chen XP, Hilton D, Rothman P. Cutting edge: SOCS-1 is a potent inhibitor of IL-4 signal transduction. J Immunol. 1999;162:3770–3774
  43. Seki Y, Inoue H, Nagata N, Hayashi K, Fukuyama S, Matsumoto K, et al. SOCS-3 regulates onset and maintenance of T(H)2-mediated allergic responses. Nat Med. 2003;9:1047–1054
  44. Yasukawa H, Ohishi M, Mori H, Murakami M, Chinen T, Aki D, et al. IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Nat Immunol. 2003;4:551–556
  45. Chen Z, Laurence A, Kanno Y, Pacher-Zavisin M, Zhu BM, Tato C, et al. Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc Natl Acad Sci U S A. 2006;103:8137–8142
  46. Sergejeva S, Ivanov S, Lotvall J, Linden A. Interleukin-17 as a recruitment and survival factor for airway macrophages in allergic airway inflammation. Am J Respir Cell Mol Biol. 2005;33:248–253
  47. Linden A, Adachi M. Neutrophilic airway inflammation and IL-17. Allergy. 2002;57:769–775
  48. Hilton DJ, Richardson RT, Alexander WS, Viney EM, Willson TA, Sprigg NS, et al. Twenty proteins containing a C-terminal SOCS box form five structural classes. Proc Natl Acad Sci U S A. 1998;95:114–119
  49. Kario E, Marmor MD, Adamsky K, Citri A, Amit I, Amariglio N, et al. Suppressors of cytokine signaling 4 and 5 regulate epidermal growth factor receptor signaling. J Biol Chem. 2005;280:7038–7048
  50. Seki Y, Hayashi K, Matsumoto A, Seki N, Tsukada J, Ransom J, et al. Expression of the suppressor of cytokine signaling-5 (SOCS5) negatively regulates IL-4-dependent STAT6 activation and Th2 differentiation. Proc Natl Acad Sci U S A. 2002;99:13003–13008
  51. Brender C, Columbus R, Metcalf D, Handman E, Starr R, Huntington N, et al. SOCS5 is expressed in primary B and T lymphoid cells but is dispensable for lymphocyte production and function. Mol Cell Biol. 2004;24:6094–6103
  52. Zeidler MP, Bach EA, Perrimon N. The roles of the Drosophila JAK/STAT pathway. Oncogene. 2000;19:2598–2606
  53. Krebs DL, Uren RT, Metcalf D, Rakar S, Zhang JG, Starr R, et al. SOCS-6 binds to insulin receptor substrate 4, and mice lacking the SOCS-6 gene exhibit mild growth retardation. Mol Cell Biol. 2002;22:4567–4578
  54. Krebs DL, Metcalf D, Merson TD, Voss AK, Thomas T, Zhang JG, et al. Development of hydrocephalus in mice lacking SOCS7. Proc Natl Acad Sci U S A. 2004;101:15446–15451
  55. Martens N, Uzan G, Wery M, Hooghe R, Hooghe-Peters EL, Gertler A. Suppressor of cytokine signaling 7 inhibits prolactin, growth hormone, and leptin signaling by interacting with STAT5 or STAT3 and attenuating their nuclear translocation. J Biol Chem. 2005;280:13817–13823
  56. Banks AS, Li J, McKeag L, Hribal ML, Kashiwada M, Accili D, et al. Deletion of SOCS7 leads to enhanced insulin action and enlarged islets of Langerhans. J Clin Invest. 2005;115:2462–2471
  57. Ihle JN. The Stat family in cytokine signaling. Curr Opin Cell Biol. 2001;13:211–217
  58. O'Shea JJ, Gadina M, Schreiber RD. Cytokine signaling in 2002: new surprises in the Jak/Stat pathway. Cell. 2002;109(suppl):S121–S131
  59. Federici M, Giustizieri ML, Scarponi C, Girolomoni G, Albanesi C. Impaired IFN-gamma-dependent inflammatory responses in human keratinocytes overexpressing the suppressor of cytokine signaling 1. J Immunol. 2002;169:434–442
  60. Ekelund E, Saaf A, Tengvall-Linder M, Melen E, Link J, Barker J, et al. Elevated expression and genetic association links the SOCS3 gene to atopic dermatitis. Am J Hum Genet. 2006;78:1060–1065

 Supported by National Institutes of Health grants RO1 DK-67231 and AI-054821 to P.B.R.Disclosure of potential conflict of interest: J. Knisz and P. B. Rothman have received grant support from the National Institutes of Health.

PII: S0091-6749(06)03812-7

doi:10.1016/j.jaci.2006.12.620

The Journal of Allergy and Clinical Immunology
Volume 119, Issue 3 , Pages 739-745, March 2007

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