Suppressor of cytokine signaling 1 regulates the immune response to infection by a unique inhibition of type I interferon activity

Suppressor of cytokine signaling 1 (SOCS1) is a critical regulator of cytokine signaling and immune responses. SOCS1-deficient mice develop severe inflammatory disease, but are very resistant to viral infections. Using neutralizing antibody to type I interferon (IFN-α and IFN-β) and mice deficient in interferon-γ or type I interferon receptor components (IFNAR1 or IFNAR2), we demonstrate here that SOCS1 deficiency amplified type I interferon antiviral and proinflammatory actions independently of interferon-γ. The mechanism of the suppression of type I interferon responses by SOCS1 was distinct from that of other cytokines. SOCS1 associated with and regulated IFNAR1- but not IFNAR2-specific signals, abrogating tyrosine phosphorylation of transcription factor STAT1 and reducing the duration of antiviral gene expression. Thus, SOCS1 is an important in vivo inhibitor of type I interferon signaling and contributes to balancing its beneficial antiviral versus detrimental proinflammatory effects on innate immunity.

[1]  C. Biron.  Cytokines in the generation of immune responses to, and resolution of, virus infection. , 1994, Current opinion in immunology.

[2]  Josef M. Penninger,et al.  CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling , 2001, Nature.

[3]  N. Copeland,et al.  A novel cytokine‐inducible gene CIS encodes an SH2‐containing protein that binds to tyrosine‐phosphorylated interleukin 3 and erythropoietin receptors. , 1995, The EMBO journal.

[4]  J U Gutterman,et al.  Cytokine therapeutics: lessons from interferon alpha. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[5]  W. Alexander,et al.  Suppressor of cytokine signaling-1 regulates signaling in response to interleukin-2 and other gamma c-dependent cytokines in peripheral T cells. , 2003, The Journal of biological chemistry.

[6]  W. Alexander,et al.  Neutralization of interferon‐γ in neonatal SOCS1−/− mice prevents fatty degeneration of the liver but not subsequent fatal inflammatory disease , 2001, Immunology.

[7]  W. Alexander,et al.  Twenty proteins containing a C-terminal SOCS box form five structural classes. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[8]  F. Belardelli,et al.  Type i interferons potently enhance humoral immunity and can promote isotype switching by stimulating dendritic cells in vivo. , 2001, Immunity.

[9]  G. Stark,et al.  How cells respond to interferons. , 1998, Annual review of biochemistry.

[10]  A. Bradley,et al.  Multiple defects of immune cell function in mice with disrupted interferon-gamma genes. , 1993, Science.

[11]  J. Johnston,et al.  Cytokine‐inducible SH2 protein‐3 (CIS3/SOCS3) inhibits Janus tyrosine kinase by binding through the N‐terminal kinase inhibitory region as well as SH2 domain , 1999, Genes to cells : devoted to molecular & cellular mechanisms.

[12]  J. G. Zhang,et al.  Suppressor of cytokine signaling-3 preferentially binds to the SHP-2-binding site on the shared cytokine receptor subunit gp130. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Y. Matsuzawa,et al.  Type I interferons and limitin: a comparison of structures, receptors, and functions. , 2001, Cytokine & growth factor reviews.

[14]  I. Kola,et al.  Endogenous IFN-alpha beta suppresses colony-stimulating factor (CSF)-1-stimulated macrophage DNA synthesis and mediates inhibitory effects of lipopolysaccharide and TNF-alpha. , 1996, Journal of immunology.

[15]  Masato Kubo,et al.  Suppressors of cytokine signaling and immunity , 2003, Nature Immunology.

[16]  K C Zoon,et al.  Interferons and their actions. , 1987, Annual review of biochemistry.

[17]  K Yuge,et al.  A Janus kinase inhibitor, JAB, is an interferon-gamma-inducible gene and confers resistance to interferons. , 1998, Blood.

[18]  M Aguet,et al.  Functional role of type I and type II interferons in antiviral defense. , 1994, Science.

[19]  M. Sweet,et al.  A Novel Pathway Regulating Lipopolysaccharide-Induced Shock by ST2/T1 Via Inhibition of Toll-Like Receptor 4 Expression1 , 2001, The Journal of Immunology.

[20]  P. Hertzog.  Isolation of embryonic fibroblasts and their use in the in vitro characterization of gene function. , 2001, Methods in molecular biology.

[21]  C. Weissmann,et al.  The interferon genes. , 1986, Progress in nucleic acid research and molecular biology.

[22]  I. Mackay,et al.  Interferons in rheumatoid arthritis: alterations in production and response related to disease activity. , 1988, Clinical immunology and immunopathology.

[23]  Paul J Hertzog,et al.  SOCS1 Is a Critical Inhibitor of Interferon γ Signaling and Prevents the Potentially Fatal Neonatal Actions of this Cytokine , 1999, Cell.

[24]  I. Gresser.  How does interferon inhibit tumor growth? , 1985, Interferon.

[25]  Y. Uchiyama,et al.  Accelerated apoptosis of lymphocytes by augmented induction of Bax in SSI-1 (STAT-induced STAT inhibitor-1) deficient mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[26]  W. Alexander,et al.  Mutational analyses of the SOCS proteins suggest a dual domain requirement but distinct mechanisms for inhibition of LIF and IL‐6 signal transduction , 1999, The EMBO journal.

[27]  Takaho A. Endo,et al.  A new protein containing an SH2 domain that inhibits JAK kinases , 1997, Nature.

[28]  A. Yoshimura,et al.  SOCS1 Deficiency Causes a Lymphocyte-Dependent Perinatal Lethality , 1999, Cell.

[29]  W. Alexander,et al.  The SOCS box: a tale of destruction and degradation. , 2002, Trends in biochemical sciences.

[30]  A. Yoshimura,et al.  The JAK‐binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop , 1999, The EMBO journal.

[31]  J. Lindenmann,et al.  Virus interference. I. The interferon , 1957, Proceedings of the Royal Society of London. Series B - Biological Sciences.

[32]  E. Stanley,et al.  Suppressor of cytokine signaling-1 is a critical regulator of interleukin-7-dependent CD8+ T cell differentiation. , 2003, Immunity.

[33]  W. Alexander,et al.  The lethal effects of transplantation of Socs1-/- bone marrow cells into irradiated adult syngeneic recipients , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[34]  W. Alexander,et al.  Suppressor of Cytokine Signaling-1 Regulates Signaling in Response to Interleukin-2 and Other γc-dependent Cytokines in Peripheral T Cells* , 2003, Journal of Biological Chemistry.

[35]  I. Gresser.  How does interferon inhibit tumour growth? , 1982, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[36]  J. Darnell,et al.  Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. , 1994, Science.

[37]  Paul J Hertzog,et al.  The interferon in TLR signaling: more than just antiviral. , 2003, Trends in immunology.

[38]  J. Walsh.  The interferons. , 1985, Medical laboratory sciences.

[39]  T. Taniguchi,et al.  Cross talk between interferon-gamma and -alpha/beta signaling components in caveolar membrane domains. , 2000, Science.

[40]  A. Elefanty,et al.  Liver degeneration and lymphoid deficiencies in mice lacking suppressor of cytokine signaling-1. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[41]  Warren S. Alexander,et al.  A family of cytokine-inducible inhibitors of signalling , 1997, Nature.

[42]  J. G. Zhang,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. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[43]  M. Tymms,et al.  A gene on human chromosome 21 located in the region 21q22.2 to 21q22.3 encodes a factor necessary for signal transduction and antiviral response to type I interferons. , 1994, The Journal of biological chemistry.

[44]  K. Shuai,et al.  The Suppressor of Cytokine Signaling (SOCS) 1 and SOCS3 but Not SOCS2 Proteins Inhibit Interferon-mediated Antiviral and Antiproliferative Activities* , 1998, The Journal of Biological Chemistry.

[45]  S. Akira,et al.  Structure and function of a new STAT-induced STAT inhibitor , 1997, Nature.

[46]  K. Struhl.  Fundamentally Different Logic of Gene Regulation in Eukaryotes and Prokaryotes , 1999, Cell.

[47]  M. Lackmann,et al.  Proapoptotic BH3-only proteins trigger membrane integration of prosurvival Bcl-w and neutralize its activity , 2003, The Journal of cell biology.

[48]  B. Neel,et al.  Role of phosphatases in lymphocyte activation. , 1997, Current opinion in immunology.

[49]  J. G. Zhang,et al.  Suppressor of cytokine signaling-1 attenuates the duration of interferon gamma signal transduction in vitro and in vivo. , 2001, The Journal of biological chemistry.

[50]  M. Smyth,et al.  NKT cells: facts, functions and fallacies. , 2000, Immunology today.

[51]  D. Hilton,et al.  Growth Hormone Preferentially Induces the Rapid, Transient Expression of SOCS-3, a Novel Inhibitor of Cytokine Receptor Signaling* , 1998, The Journal of Biological Chemistry.

[52]  M. Tymms,et al.  A null mutation in the gene encoding a type I interferon receptor component eliminates antiproliferative and antiviral responses to interferons alpha and beta and alters macrophage responses. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[53]  J. Flier,et al.  Identification of SOCS-3 as a potential mediator of central leptin resistance. , 1998, Molecular cell.

[54]  D. Hilton,et al.  Negative Regulation of Interleukin-12 Signaling by Suppressor of Cytokine Signaling-1* , 2002, The Journal of Biological Chemistry.

[55]  R. Schreiber,et al.  A critical function for type I interferons in cancer immunoediting , 2005, Nature Immunology.

[56]  M Aguet,et al.  The IFN gamma receptor: a paradigm for cytokine receptor signaling. , 1997, Annual review of immunology.