Expression of suppressors of cytokine signaling during liver regeneration
Jean S. Campbell, Lisa Prichard, Fred Schaper, Jochen Schmitz, Alyssa Stephenson-Famy, Maryland E. Rosenfeld, Gretchen M. Argast, Peter C. Heinrich, Nelson Fausto
Jean S. Campbell, Lisa Prichard, Fred Schaper, Jochen Schmitz, Alyssa Stephenson-Famy, Maryland E. Rosenfeld, Gretchen M. Argast, Peter C. Heinrich, Nelson Fausto
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Article

Expression of suppressors of cytokine signaling during liver regeneration

Abstract

The cytokines TNF and IL-6 play a critical role early in liver regeneration following partial hepatectomy (PH). Since IL-6 activates signal transducers and activators of transcription (STATs), we examined whether the suppressors of cytokine signaling (SOCS) may be involved in terminating IL-6 signaling. We show here that SOCS-3 mRNA is induced 40-fold 2 hours after surgery. SOCS-2 and CIS mRNA are only weakly induced, and SOCS-1 is not detectable. SOCS-3 induction after PH is transient and correlates with a decrease in STAT-3 DNA binding and a loss of tyrosine 705 phosphorylation. This response is markedly reduced in IL-6 knockout (KO) mice. TNF injection induces SOCS-3 mRNA in wild-type mice (albeit weakly compared with the increase observed after PH) but not in TNF receptor 1 or IL-6 KO mice. In contrast, IL-6 injection induces SOCS-3 in these animals, demonstrating a requirement for IL-6 in SOCS-3 induction. IL-6 injection into wild-type mice also induces SOCS-1, -2, and CIS mRNA, in addition to SOCS-3. Together, these results suggest that SOCS-3 may be a key component in downregulating STAT-3 signaling after PH and that SOCS-3 mRNA levels in the regenerating liver are regulated by IL-6.

Authors

Jean S. Campbell, Lisa Prichard, Fred Schaper, Jochen Schmitz, Alyssa Stephenson-Famy, Maryland E. Rosenfeld, Gretchen M. Argast, Peter C. Heinrich, Nelson Fausto

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Blunted induction of SOCS-3 mRNA and protein in IL-6 KO mice after PH. T...
Blunted induction of SOCS-3 mRNA and protein in IL-6 KO mice after PH. Total RNA was prepared from the remnant liver at the indicated times after PH as described in Methods. (a) Total RNA was probed for SOCS-3 and cyclophilin message levels as described in Methods. Molecular-weight markers are shown on the left in kilobases. (b) Induction of SOCS-3 mRNA was quantified by phosphorimager analysis as described in Figure 2. The error bars represent SEM of the data from three independent experiments. AP < 0.001 vs. IL-6 KO, 3-hour PH values. (c) Whole-cell lysates were prepared from the remnant liver at the indicated times after PH. SOCS-3 protein was detected by immunoblot analysis using SDS-PAGE (top panel). The blot was stripped and reprobed for β-actin (bottom panel). Molecular-weight markers are shown on the left in kilodaltons.