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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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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Induction of SOCS-3 mRNA and protein after PH in WT mice. Total RNA was ...
Induction of SOCS-3 mRNA and protein after PH in WT mice. 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 mRNA 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 relative to cyclophilin levels. The error bars represent SEM of the data from three independent experiments. AP < 0.01, BP < 0.001 vs. control 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). As a positive control, cell lysate from IL-6–stimulated RAW 264.7 cells is shown on the right and molecular-weight markers are shown on the left in kilodaltons. To ensure equal loading, the blot was stripped and reprobed for β-actin (bottom panel).