Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Suppressors of cytokine signaling and immunity

Nature Immunology volume 4, pages 1169–1176 (2003)Cite this article

Abstract

The suppressors of cytokine signaling (SOCS) and cytokine-inducible SH2 protein are key physiological regulators of the immune system. Principally, SOCS1 and SOCS3 regulate T cells as well as antigen-presenting cells, including macrophages and dendritic cells. Here we review the function of SOCS1 and SOCS3 in innate and adaptive immunity, with particular emphasis on the relationship between immune regulation and SOCS.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The molecular mechanism by which SOCS proteins negatively regulate cytokine signaling.
Figure 2: SOCS1 and T cell regulation.
Figure 3: Macrophage and dendritic cell regulation by SOCS.
Figure 4: SOCS3 regulates inflammatory diseases by suppressing IL-6-related cytokines.

Similar content being viewed by others

References

  1. Nicola, N.A. (ed.) Guidebook to Cytokines and Their Receptors (Oxford University Press, Oxford, 1994).

    Google Scholar 

  2. Ihle, J.N. Cytokine receptor signalling. Nature 377, 591–594 (1995).

    Article  CAS  Google Scholar 

  3. O'Shea, J.J., Gadina, M. & Schreiber, R.D. Cytokine signaling in 2002: new surprises in the Jak/Stat pathway. Cell. 109, S121–131 (2002).

    Article  CAS  Google Scholar 

  4. Yasukawa, H., Sasaki A. & Yoshimura A. Negative regulation of cytokine signaling pathways. Annu. Rev. Immunol. 18, 143–164 (2000).

    Article  CAS  Google Scholar 

  5. Alexander, W.S. Suppressors of cytokine signalling (SOCS) in the immune system. Nat. Rev. Immunol. 2, 410–416 (2002).

    Article  CAS  Google Scholar 

  6. Greenhalgh, C.J., Miller, M.E., Hilton, D.J. & Lund, P.K. Suppressors of cytokine signaling: relevance to gastrointestinal function and disease. Gastroenterology 123, 2064–2081 (2002).

    Article  CAS  Google Scholar 

  7. Naka, T. et al. Structure and function of a new STAT-induced STAT inhibitor. Nature 387, 924–929 (1997).

    Article  CAS  Google Scholar 

  8. Starr, R. et al. A family of cytokine-inducible inhibitors of signalling. Nature 387, 917–921 (1997).

    Article  CAS  Google Scholar 

  9. Endo, T.A. et al. A new protein containing an SH2 domain that inhibits JAK kinases. Nature 387, 921–924 (1997).

    Article  CAS  Google Scholar 

  10. Yoshimura, A. 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. 14: 2816–2826 (1995).

    Article  CAS  Google Scholar 

  11. Ram, P.A. & Waxman, D.J. SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling by multiple mechanisms. J. Biol. Chem. 274, 35553–35561 (1999).

    Article  CAS  Google Scholar 

  12. Favre, H., Benhamou, A., Finidori, J., Kelly, P.A. & Edery, M. Dual effects of suppressor of cytokine signaling (SOCS-2) on growth hormone signal transduction. FEBS Lett.; 453: 63–66 (1999).

    Article  CAS  Google Scholar 

  13. Greenhalgh, C.J. et al. Biological evidence that SOCS-2 can act either as an enhancer or suppressor of growth hormone signaling. J. Biol. Chem. 277, 40181–40184 (2002).

    Article  CAS  Google Scholar 

  14. Greenhalgh, C.J. et al. Growth enhancement in suppressor of cytokine signaling 2 (SOCS-2)-deficient mice is dependent on signal transducer and activator of transcription 5b (STAT5b). Mol. Endocrinol. 16, 1394–1406 (2002).

    Article  CAS  Google Scholar 

  15. Metcalf, D. et al. Gigantism in mice lacking suppressor of cytokine signalling-2. Nature 405, 1069–1073 (2000).

    Article  CAS  Google Scholar 

  16. Seki, Y. 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. USA 99, 13003–13008 (2002).

    Article  CAS  Google Scholar 

  17. Yasukawa, H. et al. The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop. EMBO J. 18, 1309–1320 (1999).

    Article  CAS  Google Scholar 

  18. Giordanetto, F. & Kroemer, R.T. A three-dimensional model of suppressor of cytokine signalling 1 (SOCS-1). Protein Eng. 16, 115–124 (2003).

    Article  CAS  Google Scholar 

  19. Sasaki, A. et al. CIS3/SOCS-3 suppresses erythropoietin (EPO) signaling by binding the EPO receptor and JAK2. J. Biol. Chem. 275, 29338–29347 (2000).

    Article  CAS  Google Scholar 

  20. Nicholson, S.E. 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. USA 97, 6493–6498 (2000).

    Article  CAS  Google Scholar 

  21. Lehmann, U. et al. SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6 signaling through gp130. J. Biol. Chem. 278, 661–671 (2003).

    Article  CAS  Google Scholar 

  22. Hortner, M., Nielsch, U., Mayr, L.M., Heinrich, P.C. & Haan, S. A new high affinity binding site for suppressor of cytokine signaling-3 on the erythropoietin receptor. Eur. J. Biochem. 269, 2516–2526 (2002).

    Article  CAS  Google Scholar 

  23. Bjorbaek, C. et al. SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985. J. Biol. Chem. 275, 40649–40657 (2000).

    Article  CAS  Google Scholar 

  24. De Souza, D. et al. SH2 domains from suppressor of cytokine signaling-3 and protein tyrosine phosphatase SHP-2 have similar binding specificities. Biochemistry 41, 9229–9236 (2002).

    Article  CAS  Google Scholar 

  25. Kamura, T. 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. 12, 3872–3881 (1998).

    Article  CAS  Google Scholar 

  26. Zhang, J.G. et al. The conserved SOCS box motif in suppressors of cytokine signaling binds to elongins B and C and may couple bound proteins to proteasomal degradation. Proc. Natl. Acad. Sci. USA 96, 2071–2076 (1999).

    Article  CAS  Google Scholar 

  27. Kamizono, S. et al. The SOCS box of SOCS-1 accelerates ubiquitin-dependent proteolysis of TEL-JAK2. J. Biol. Chem. 276, 12530–12538 (2001).

    Article  CAS  Google Scholar 

  28. Frantsve, J., Schwaller, J., Sternberg, D.W., Kutok, J. & Gilliland, D.G. 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. 21, 3547–3557 (2001).

    Article  CAS  Google Scholar 

  29. Zhang, J.G. et al. The SOCS box of suppressor of cytokine signaling-1 is important for inhibition of cytokine action in vivo. Proc. Natl. Acad. Sci. USA 98, 13261–13265 (2001).

    Article  CAS  Google Scholar 

  30. Haan, S. et al. Tyrosine phosphorylation disrupts elongin interaction and accelerates SOCS3 degradation. J. Biol. Chem. 278, 31972–31979 (2003).

    Article  CAS  Google Scholar 

  31. Naka, T. et al. Accelerated apoptosis of lymphocytes by augmented induction of Bax in SSI-1 (STAT-induced STAT inhibitor-1)-deficient mice. Proc. Natl. Acad. Sci. USA 95, 15577–15582 (1998).

    Article  CAS  Google Scholar 

  32. Starr, R. et al. Liver degeneration and lymphoid deficiencies in mice lacking suppressor of cytokine signaling-1. Proc. Natl. Acad. Sci. USA 95, 14395–14399 (1998).

    Article  CAS  Google Scholar 

  33. Marine, J.C. et al. SOCS1 deficiency causes a lymphocyte-dependent perinatal lethality. Cell 98, 609–616 (1999).

    Article  CAS  Google Scholar 

  34. Alexander, W.S. et al. SOCS1 is a critical inhibitor of interferon-signaling and prevents the potentially fatal neonatal actions of this cytokine. Cell 98, 597–608 (1999).

    Article  CAS  Google Scholar 

  35. Bullen, D.V., Darwiche, R., Metcalf, D., Handman, E. & Alexander, W.S. Neutralization of interferon- in neonatal SOCS1−/− mice prevents fatty degeneration of the liver but not subsequent fatal inflammatory disease. Immunology 104, 92–98 (2001).

    Article  CAS  Google Scholar 

  36. Metcalf, D. et al. Polycystic kidneys and chronic inflammatory lesions are the delayed consequences of loss of the suppressor of cytokine signaling-1 (SOCS-1). Proc. Natl. Acad. Sci. USA 99, 943–948 (2002).

    Article  CAS  Google Scholar 

  37. Hanada, T. et al. Suppressor of cytokine signaling-1 is essential for suppressing dendritic cell activation and systemic autoimmunity. Immunity 19, 437–450 (2003).

    Article  CAS  Google Scholar 

  38. Sporri, B., Kovanen, P.E., Sasaki, A., Yoshimura, A. & Leonard, W.J. JAB/SOCS1/SSI-1 is an interleukin-2-induced inhibitor of IL-2 signaling. Blood 97, 221–226 (2001).

    Article  CAS  Google Scholar 

  39. Cornish, A.L. et al. Suppressor of cytokine signaling-1 regulates signaling in response to interleukin-2 and other γ c-dependent cytokines in peripheral T cells. J. Biol. Chem. 278, 22755–22761 (2003).

    Article  CAS  Google Scholar 

  40. Diehl, S. et al. Inhibition of TH1 differentiation by IL-6 is mediated by SOCS1. Immunity 13, 805–815 (2000).

    Article  CAS  Google Scholar 

  41. Eyles, J.L., Metcalf, D., Grusby, M.J., Hilton, D.J. & Starr, R. Negative regulation of interleukin-12 signaling by suppressor of cytokine signaling-1. J. Biol. Chem. 277, 43735–43740 (2002).

    Article  CAS  Google Scholar 

  42. Ilangumaran, S., Ramanathan, S., La Rose, J., Poussier, P. & Rottapel, R. Suppressor of cytokine signaling 1 regulates IL-15 receptor signaling in CD8+CD44high memory T lymphocytes. J. Immunol. 171, 2435–2445 (2003).

    Article  CAS  Google Scholar 

  43. Ilangumaran, S. et al. Suppressor of cytokine signaling 1 attenuates IL-15 receptor signaling in CD8+ thymocytes. Blood prepublished online, 7 August 2003 (doi:10.1182/blood-2003-01-0175).

  44. Morita, Y. et al. Signals transducers and activators of transcription (STAT)-induced STAT inhibitor-1 (SSI-1)/suppressor of cytokine signaling-1 (SOCS-1) suppresses tumor-necrosis-factor—induced cell death in fibroblasts. Proc. Natl. Acad. Sci. USA 97, 5405–5410 (2000).

    Article  CAS  Google Scholar 

  45. Kinjyo, I. et al. SOCS1/JAB is a negative regulator of LPS-induced macrophage activation. Immunity 17, 583–591 (2002).

    Article  CAS  Google Scholar 

  46. Nakagawa, R. et al. SOCS-1 participates in negative regulation of LPS responses. Immunity 17, 677–687 (2002).

    Article  CAS  Google Scholar 

  47. Kawazoe, Y. et al. Signal transducer and activator of transcription (STAT)-induced STAT inhibitor 1 (SSI-1)/suppressor of cytokine signaling 1 (SOCS1) inhibits insulin signal transduction pathway through modulating insulin receptor substrate 1 (IRS-1) phosphorylation. J. Exp. Med. 193, 263–269 (2001).

    Article  CAS  Google Scholar 

  48. De Sepulveda, P. et al. Socs1 binds to multiple signalling proteins and suppresses steel factor-dependent proliferation. EMBO J. 18, 904–915 (1999).

    Article  CAS  Google Scholar 

  49. Naka, T. et al. SOCS-1/SSI-1-deficient NKT cells participate in severe hepatitis through dysregulated cross-talk inhibition of IFN- and IL-4 signaling in vivo. Immunity 14, 535–545 (2001).

    Article  CAS  Google Scholar 

  50. Metcalf, D., Mifsud, S., Di Rago, L. & Alexander, W.S. The lethal effects of transplantation of Socs1−/− bone marrow cells into irradiated adult syngeneic recipients Proc. Natl. Acad. Sci. USA 100, 8436–8441 (2003).

    Article  CAS  Google Scholar 

  51. Chong, M.M. et al. Suppressor of cytokine signaling-1 is a critical regulator of interleukin-7-dependent CD8+ T cell differentiation. Immunity 18, 475–487 (2003).

    Article  CAS  Google Scholar 

  52. Cornish, A.L. et al. Suppressor of cytokine signaling-1 has IFN-independent actions in T cell homeostasis J. Immunol. 170, 878–886 (2003).

    Article  CAS  Google Scholar 

  53. Lewis, D.B. et al. Interleukin 4 expressed in situ selectively alters thymocyte development. J. Exp. Med. 173, 89–100 (1991).

    Article  CAS  Google Scholar 

  54. McHugh, R.S. et al. CD4+CD25+ immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 16, 311–323 (2002).

    Article  CAS  Google Scholar 

  55. Naka, T. et al. Inadequate induction of suppressor of cytokine signaling-1 causes systemic autoimmune diseases. Int. Immunol. (in the press).

  56. Pasare, C. & Medzhitov, R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299, 1033–1036 (2003).

    Article  CAS  Google Scholar 

  57. Fujimoto, M. et al. A regulatory role for suppressor of cytokine signaling-1 in Th polarization in vivo. Int. Immunol. 14, 1343–1350 (2002).

    Article  CAS  Google Scholar 

  58. Egan, P.J., Lawlor, K.E., Alexander, W.S. & Wicks, I.P. Suppressor of cytokine signaling-1 regulates acute inflammatory arthritis and T cell activation. J. Clin. Invest. 111, 915–924 (2003).

    Article  CAS  Google Scholar 

  59. Egwuagu, C.E. et al. Suppressors of cytokine signaling proteins are differentially expressed in Th1 and Th2 cells: implications for Th cell lineage commitment and maintenance. J. Immunol. 168, 3181–3187 (2002).

    Article  CAS  Google Scholar 

  60. Roberts, A.W. et al. Placental defects and embryonic lethality in mice lacking suppressor of cytokine signaling 3. Proc. Natl. Acad. Sci. USA 98, 9324–9329 (2003).

    Article  Google Scholar 

  61. Takahashi, Y. et al. SOCS3: an essential regulator of LIF receptor signaling in trophoblast giant cell differentiation. EMBO J. 22, 372–384 (2003).

    Article  CAS  Google Scholar 

  62. Seki, Y. et al. SOCS-3 regulates onset and maintenance of TH2-mediated allergic responses Nat. Med. 9, 1047–1054 (2003).

    Article  CAS  Google Scholar 

  63. Cohney, S.J. et al. SOCS-3 is tyrosine phosphorylated in response to interleukin-2 and suppresses STAT5 phosphorylation and lymphocyte proliferation. Mol. Cell Biol. 19, 4980–4988 (1999).

    Article  CAS  Google Scholar 

  64. Banerjee, A., Banks, A.S., Nawijn, M.C., Chen, X.P. & Rothman, P.B. Cutting edge: Suppressor of cytokine signaling 3 inhibits activation of NFATp. J. Immunol. 168, 4277–4281 (2002).

    Article  CAS  Google Scholar 

  65. Matsumoto, A. et al. A role of suppressor of cytokine signaling 3 (SOCS3/CIS3/SSI3) in CD28-mediated interleukin 2 production. J. Exp. Med. 197, 425–436 (2003).

    Article  CAS  Google Scholar 

  66. Crepso, A., Filla, M.B., Russell, S.W. & Murphy, W.J. Indirect induction of suppressor of cytokine signaling-1 in macrophages stimulated with bacterial lipopolysaccharide: partial role of autocrine/paracrine interferon-α/β. Biochem. J. 349, 99–104 (2000).

    Article  Google Scholar 

  67. Bode, J.G. et al. LPS and TNFalpha induce SOCS3 mRNA and inhibit IL-6-induced activation of STAT3 in macrophages. LPS and TNFα induce SOCS3 mRNA and inhibit IL-6-induced activation of STAT3 in macrophages. FEBS Lett. 463, 365–370 (1999).

    Article  CAS  Google Scholar 

  68. Dalpke, A.H., Opper, S., Zimmermann, S. & Heeg, K. Suppressors of cytokine signaling (SOCS)-1 and SOCS-3 are induced by CpG-DNA and modulate cytokine responses in APCs. J. Immunol. 166, 7082–7089 (2001).

    Article  CAS  Google Scholar 

  69. Takeda, K. et al. Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 10, 39–49 (1999).

    Article  CAS  Google Scholar 

  70. Yasukawa, H. et al. IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Nat. Immunol. 4, 551–556 (2003).

    Article  CAS  Google Scholar 

  71. Cheng, F. et al. A critical role for Stat3 signaling in immune tolerance. Immunity 19, 425–436 (2003).

    Article  CAS  Google Scholar 

  72. Lang, R. et al. SOCS3 regulates the plasticity of gp130 signaling. Nat. Immunol. 4, 546–550 (2003).

    Article  CAS  Google Scholar 

  73. Croker, B.A. et al. SOCS3 negatively regulates IL-6 signaling in vivo. Nat. Immunol. 4, 540–555 (2003).

    Article  CAS  Google Scholar 

  74. Brod, S.A. Ingested type I interferon: a potential treatment for autoimmunity. J. Interferon Cytokine Res. 22, 1153–11566 (2002).

    Article  CAS  Google Scholar 

  75. Atsumi, T. et al. A point mutation of Tyr-759 in interleukin 6 family cytokine receptor subunit gp130 causes autoimmune arthritis. J. Exp. Med. 196, 979–990 (2002).

    Article  CAS  Google Scholar 

  76. Tebbutt, N.C. et al. Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice. Nat. Med. 8, 1089–1097 (2002).

    Article  CAS  Google Scholar 

  77. Suzuki, A. et al. CIS3/SOCS3/SSI3 plays a negative regulatory role in STAT3 activation and intestinal inflammation. J. Exp. Med. 193, 471–481 (2001).

    Article  CAS  Google Scholar 

  78. Shouda, T. et al. Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis. J. Clin. Invest. 108, 1781–1788 (2001).

    Article  CAS  Google Scholar 

  79. Matsumoto, A. 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. 19, 6396–6407 (1999).

    Article  CAS  Google Scholar 

  80. Li, S. et al. Cytokine-induced Src-homology 2 protein (CIS) promotes T-cell receptor-mediated proliferation and prolongs survival of activated T cells. J. Exp. Med. 191, 985–994 (2000).

    Article  CAS  Google Scholar 

  81. Krebs, D.L. et al. SOCS-6 binds to insulin receptor substrate 4, and mice lacking the SOCS-6 gene exhibit mild growth retardation. Mol. Cell Biol. 22, 4567–4578 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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

Author information

Authors and Affiliations

  1. Department of Immunobiology, Research Institute for Biological Sciences, Tokyo University of Science, Noda, 278-0022, Japan

    Masato Kubo

  2. Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Toshikatsu Hanada & Akihiko Yoshimura

Authors
  1. Masato Kubo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Toshikatsu Hanada
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Akihiko Yoshimura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Akihiko Yoshimura.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kubo, M., Hanada, T. & Yoshimura, A. Suppressors of cytokine signaling and immunity. Nat Immunol 4, 1169–1176 (2003). https://doi.org/10.1038/ni1012

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1012

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing