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-gamma (IFNgamma) 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 IFNgamma signaling. Surprisingly, heightened Socs1 mRNA expression but minimal STAT1 tyrosine phosphorylation was observed after prolonged stimulation with IFNgamma, indicating that STAT1 may not play a large role in inducing Socs1 mRNA during steady-state IFNgamma signaling. We also demonstrate that both SOCS1 and SOCS3 can desensitize primary bone marrow-derived macrophages to IFNgamma 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 IFNgamma 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.
Highlights
Ing IFN␥-receptor  subunit, whereas the IL-6-receptor complex consists of the ligand-binding IL-6-receptor ␣ subunit and the signal-transducing glycoprotein-130 subunit [1]
Differential Induction of signal transducer and activator of transcription-1 (STAT1) and STAT3 Tyrosine Phosphorylation by IFN␥ and IL-6 in the Liver—Gene deletion studies in mice have revealed the importance of suppressor of cytokine signaling-1 (SOCS1) for regulating IFN␥ and SOCS3 for regulating IL-6 signaling, little is known of the comparative induction of suppressor of cytokine signaling (SOCS) proteins by IFN␥ and IL-6
To further clarify the importance of SOCS proteins in regulating signaling by IFN␥ and IL-6, we compared the roles of SOCS1 and SOCS3 in regulating the kinetics of cytokine signal transduction
Summary
Ing IFN␥-receptor  subunit, whereas the IL-6-receptor complex consists of the ligand-binding IL-6-receptor ␣ subunit and the signal-transducing glycoprotein-130 subunit [1]. IFN␥ acts on cells to induce inflammatory and anti-viral responses, whereas IL-6 acts on cells to regulate the production of acute phase proteins (primarily in hepatocytes) as well as the growth and differentiation of a variety of cell types This paradox has been explained by an understanding that IFN␥ primarily signals via STAT1, whereas IL-6 primarily signals via STAT3 [21]. IL-6 signaling in the absence of SOCS3 resulted in the prolonged phosphorylation of STAT1 and a qualitative shift in the transcriptional response of IL-6 toward that typical of IFN␥ [16, 24, 25] This indicates that signaling by IFN␥ and IL-6 is fundamentally similar, and that the activity of SOCS3 is required to sculpt the cellular response to IL-6 and thereby discriminate it from that of IFN␥. SOCS1 and SOCS3 are attractive candidates as mediators of desensitization to IFN␥ and IL-6, respectively, detection of this activity has so far proved elusive [27]
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