The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling*
- Samuel Wormald ‡ 1 ,
- Jian-Guo Zhang ‡ ,
- Danielle L. Krebs ‡ ,
- Lisa A. Mielke ‡ ,
- Jeremy Silver § ,
- Warren S. Alexander ‡ ,
- Terence P. Speed § ,
- Nicos A. Nicola ‡ and
- Douglas J. Hilton ‡
- ‡Division of Cancer and Haematology, and the §Division of Genetics and Bioinformatics, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia
- 1Supported by an Australian Postgraduate Award. To whom correspondence should be addressed. Tel.: 61-3-9345-2500; Fax: 61-3-9347-0852; E-mail: wormald{at}wehi.edu.au.
Abstract
Negative feedback is a mechanism commonly employed in biological processes as a means of maintaining homeostasis. We have investigated the roles of suppressor of cytokine signaling (SOCS) proteins in regulating the kinetics of negative feedback in response to cytokine signaling. In mouse livers and bone marrow-derived macrophages, both interferon-γ (IFNγ) and interleukin-6 (IL-6) rapidly induced the tyrosine phosphorylation of signal transducer and activator of transcription-1 (STAT1) and STAT3. STAT3 tyrosine phosphorylation was bi-phasic in response to continuous IL-6 signaling. In macrophages lacking Socs3, however, continuous IL-6 signaling induced uniformly high levels of STAT3 tyrosine phosphorylation, and early IL-6-inducible genes were inappropriately expressed at intermediate time points. SOCS3 therefore imposes bi-phasic kinetics upon IL-6 signaling. Compared with Socs3 mRNA, Socs1 mRNA was induced relatively slowly, and SOCS1 simply attenuated the duration of IFNγ signaling. Surprisingly, heightened Socs1 mRNA expression but minimal STAT1 tyrosine phosphorylation was observed after prolonged stimulation with IFNγ, indicating that STAT1 may not play a large role in inducing Socs1 mRNA during steady-state IFNγ signaling. We also demonstrate that both SOCS1 and SOCS3 can desensitize primary bone marrow-derived macrophages to IFNγ and IL-6 signaling, respectively. Consistent with the kinetics with which Socs1 and Socs3 mRNAs were induced, SOCS3 desensitized cells to IL-6 rapidly, whereas SOCS1-mediated desensitization to IFNγ occurred at later time points. The kinetics with which SOCS proteins are induced by cytokine may therefore be a parameter that is “hard-wired” into specific cytokine signaling pathways as a means of tailoring the kinetics with which cells become desensitized.
Footnotes
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↵2 The abbreviations used are: IL-6, interluekin-6; IFNγ, interferon-γ; JAK, Janus kinase; STAT, signal transducers and activators of transcription; P-STAT, phosphorylated STAT; SOCS1, suppressor of cytokine signaling-1; LCM, L-cell-conditioned medium; PBS, phosphate-buffered saline; MTPBS, mouse-tonicity PBS; Q-PCR, quantitative PCR.
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↵3 M. Reich, K. Ohm, M. Angelo, P. Tamayo, and J. P. Mesirov (2004) GeneCluster 2.0, available at www.broad.mit.edu/cancer/software/genecluster2/gc2.html.
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↵* This work was supported in part by the Australian National Health and Medical Research Council (Program Grant 257500) and by National Institutes of Health Grant CA22556. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Received August 31, 2005.
- Revision received December 21, 2005.
- The American Society for Biochemistry and Molecular Biology, Inc.
