The comparative roles of suppressor of cytokine signaling-1 and -3 in the inhibition and desensitization of cytokine signaling

Wormald, Samuel, Hilton, Douglas J., Krebs, Danielle L., Mielke, Lisa A., Silver, Jeremy, Alexander, Warren S., Speed, Terence P., Nicola, Nicos A. and Hilton, Douglas J. (2006) The comparative roles of suppressor of cytokine signaling-1 and -3 in the inhibition and desensitization of cytokine signaling. The Journal of Biological Chemistry, 281 16: 11135-11143. doi:10.1074/jbc.M509595200

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Author Wormald, Samuel
Hilton, Douglas J.
Krebs, Danielle L.
Mielke, Lisa A.
Silver, Jeremy
Alexander, Warren S.
Speed, Terence P.
Nicola, Nicos A.
Hilton, Douglas J.
Title The comparative roles of suppressor of cytokine signaling-1 and -3 in the inhibition and desensitization of cytokine signaling
Journal name The Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
1083-351X
Publication date 2006-04-21
Sub-type Article (original research)
DOI 10.1074/jbc.M509595200
Open Access Status File (Publisher version)
Volume 281
Issue 16
Start page 11135
End page 11143
Total pages 10
Place of publication Bethesda, MD., U.S.
Publisher American Society for Biochemistry and Molecular Biology
Language eng
Subject 0604 Genetics
0605 Microbiology
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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
Institute for Molecular Bioscience - Publications
 
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Created: Tue, 16 Mar 2010, 12:06:18 EST by Therese Egan on behalf of Institute for Molecular Bioscience