Abstract
Interferon-γ and interleukin-4 (IL-4) induce distinct gene expression profiles in macrophages by differentially activating signal transducers and activators of transcription (STAT)1 and STAT6, respectively. The role of suppressor of cytokine signaling (SOCS)-1 as a negative regulator of IFN-γ signaling is well established. However, its potential role as a negative regulator of IL-4 signaling has not been explored. We found that IL-4, like IFN-γ, induces rapid de novo expression of SOCS-1 in primary macrophages. Induction of SOCS-1 gene expression by IL-4 is STAT6-dependent, whereas induction of SOCS-1 by IFN-γ is STAT1-dependent. Unlike their common ability to induce expression of SOCS-1, IL-4 also induced expression of SOCS-2 but not SOCS-3 in macrophages, whereas IFN-γ induced expression of SOCS-3 but not SOCS-2. Forced expression of SOCS-1 or SOCS-3, but not SOCS-2, inhibited activation of STAT6 by IL-4. Moreover, SOCS-1 appears to serve as an endogenous regulator of IL-4 signaling in macrophages because the magnitude and duration of STAT6 activation as well as IL-4-mediated gene expression were much greater in SOCS-1-deficient (SOCS-1−/−) macrophages than in wild-type macrophages. Our findings demonstrate that, like IFN-γ, IL-4 also induces expression of SOCS-1 in macrophages, and SOCS-1 feedback inhibits expression of STAT6-responsive genes.
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References
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.
Goerdt S, Orfanos CE . Other functions, other genes: alternative activation of antigen-presenting cells. Immunity 1999; 10: 137–142.
Gordon S . Alternative activation of macrophages. Nat Rev Immunol 2003; 3: 23–35.
Mosser DM . The many faces of macrophage activation. J Leukoc Biol 2003; 73: 209–212.
Takeda K, Tanaka T, Shi W, Matsumoto M, Minami M, Kashiwamura S et al. Essential role of Stat6 in IL-4 signalling. Nature 1996; 380: 627–630.
Shimoda K, van Deursen J, Sangster MY, Sarawar SR, Carson RT, Tripp RA et al. Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature 1996; 380: 630–633.
Alexander WS, Hilton DJ . The role of suppressors of cytokine signaling (SOCS) proteins in regulation of the immune response. Annu Rev Immunol 2004; 22: 503–529.
Dickensheets H, Venkataraman C, Schindler U, Donnelly RP . Interferons inhibit activation of STAT6 by interleukin-4 in human monocytes by inducing SOCS-1 gene expression. Proc Natl Acad Sci USA 1999; 96: 10800–10805.
Losman JA, Chen XP, Hilton D, Rothman P . SOCS-1 is a potent inhibitor of IL-4 signal transduction. J Immunol 1999; 162: 3770–3774.
Haque SJ, Harbor PC, Williams BR . Identification of critical residues required for suppressor of cytokine signaling-specific regulation of interleukin-4 signaling. J Biol Chem 2000; 275: 26500–26506.
Meraz MA, White JM, Sheehan KC, Bach EA, Rodig SJ, Dighe AS et al. Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell 1996; 84: 431–442.
Durbin JE, Hackenmiller R, Simon MC, Levy DE . Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell 1996; 84: 443–450.
Song MM, Shuai K . The suppressor of cytokine signaling (SOCS)1 and SOCS3 but not SOCS2 proteins inhibit interferon-mediated antiviral and antiproliferative activities. J Biol Chem 1998; 273: 35056–35062.
Alexander WS, Starr R, Fenner JE, Scott CL, Handman E, Sprigg NS et al. SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine. Cell 1999; 98: 597–608.
Marine JC, Topham DJ, McKay C, Wang D, Parganas E, Stravopodis D et al. SOCS1 deficiency causes a lymphocyte-dependent perinatal lethality. Cell 1999; 98: 609–616.
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.
Naka T, Tsutsui H, Fujimoto M, Kawazoe Y, Kohzaki H, Morita Y et al. SOCS-1/SSI-1-deficient NKT cells participate in severe hepatitis through dysregulated cross-talk inhibition of IFN-γ and IL-4 signaling in vivo. Immunity 2001; 14: 535–545.
Federici M, Giustizieri ML, Scarponi C, Girolomoni G, Albanesi C . Impaired IFN-γ-dependent inflammatory responses in human keratinocytes overexpressing the suppressor of cytokine signaling 1. J Immunol 2002; 168: 434–442.
Travagli J, Letourneur M, Bertoglio J, Pierre J . STAT6 and Ets-1 form a stable complex that modulates Socs-1 expression by interleukin-4 in keratinocytes. J Biol Chem 2004; 279: 35183–35192.
Heller NM, Matsukura S, Georas SN, Boothby MR, Rothman PB, Stellato C et al. Interferon-γ inhibits STAT6 signal transduction and gene expression in human airway epithelial cells. Am J Respir Cell Mol Biol 2004; 31: 573–582.
Ramana CV, Gil MP, Han Y, Ransohoff RM, Schreiber RD, Stark GR . Stat1-independent regulation of gene expression in response to IFN-gamma. Proc Natl Acad Sci USA 2001; 98: 6674–6679.
Gil MP, Bohn E, O'Guin AK, Ramana CV, Levine B, Stark GR et al. Biologic consequences of Stat1-independent IFN signaling. Proc Natl Acad Sci USA 2001; 98: 6680–6685.
Ramana CV, Kumar A, Enelow R . Stat1-independent induction of SOCS-3 by interferon-γ is mediated by sustained activation of Stat3 in mouse embryonic fibroblasts. Biochem Biophys Res Commun 2005; 327: 727–733.
Pernis AB, Rothman PB . JAK-STAT signaling in asthma. J Clin Invest 2002; 109: 1279–1283.
Chen W, Daines MO, Khurana Hershey GK . Turning off signal transducer and activator of transcription (STAT): the negative regulation of STAT signaling. J Allergy Clin Immunol 2004; 114: 476–489.
Wahl LM, Katona IM, Wilder RL, Winter CC, Haraoui B, Scher I et al. Isolation of human mononuclear cell subsets by counterflow centrifugal elutriation (CCE). I. Characterization of B-lymphocyte-, T-lymphocyte-, and monocyte-enriched fractions by flow cytometric analysis. Cell Immunol 1984; 85: 373–383.
Gingras S, Parganas E, de Pauw A, Ihle JN, Murray PJ . Re-examination of the role of suppressor of cytokine signaling 1 (SOCS1) in the regulation of toll-like receptor signaling. J Biol Chem 2004; 279: 54702–54707.
Donnelly RP, Fenton MJ, Kaufman JD, Gerrard TL . IL-1 expression in human monocytes is transcriptionally and posttranscriptionally regulated by IL-4. J Immunol 1991; 146: 3431–3436.
Starr R, Willson TA, Viney EM, Murray LJL, Rayner JR, Jenkins BJ et al. A family of cytokine-inducible inhibitors of signalling. Nature (London) 1997; 387: 917–921.
Rutschman R, Lang R, Hesse M, Ihle JN, Wynn TA, Murray PJ . Stat6-dependent substrate depletion regulates nitric oxide production. J Immunol 2001; 166: 2173–2177.
Feinberg AP, Vogelstein B . A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem 1983; 132: 6–13.
Schreiber E, Matthias P, Muller MM, Schaffner W . Rapid detection of octamer binding proteins with ‘mini-extracts’, prepared from a small number of cells. Nucleic Acids Res 1989; 17: 6419.
Dignam JD, Lebovitz RM, Roeder RG . Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res 1983; 11: 1475–1489.
Ohmori Y, Smith MF, Hamilton TA . IL-4-induced expression of the IL-1 receptor antagonist gene is mediated by STAT6. J Immunol 1996; 157: 2058–2065.
Acknowledgements
We wish to thank Drs Mark Song and Ke Shuai (UCLA, Los Angeles, CA, USA) for sharing their SOCS gene-transfected HeLa cell lines and Dr William Paul (NIAID, Bethesda, MD, USA) for providing STAT6 knockout mice. This study was supported in part by NIH Grant AI059638 to JJR and AI062921 to PJM.
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Dickensheets, H., Vazquez, N., Sheikh, F. et al. Suppressor of cytokine signaling-1 is an IL-4-inducible gene in macrophages and feedback inhibits IL-4 signaling. Genes Immun 8, 21–27 (2007). https://doi.org/10.1038/sj.gene.6364352
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DOI: https://doi.org/10.1038/sj.gene.6364352
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