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Expression of suppressors of cytokine signaling during liver regeneration
Jean S. Campbell, … , Peter C. Heinrich, Nelson Fausto
Jean S. Campbell, … , Peter C. Heinrich, Nelson Fausto
Published May 15, 2001
Citation Information: J Clin Invest. 2001;107(10):1285-1292. https://doi.org/10.1172/JCI11867.
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Article

Expression of suppressors of cytokine signaling during liver regeneration

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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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Figure 1

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Transient activation of STAT-3 after PH in WT mice. Nuclear extracts and...
Transient activation of STAT-3 after PH in WT mice. Nuclear extracts and whole-cell lysates were prepared from the remnant liver at the indicated times after PH. (a) STAT-3 was immunoprecipitated from whole-cell lysates and analyzed for phosphotyrosine 705 and phosphoserine 727 content using immunoblot analysis. The top panel is phosphotyrosine 705–STAT-3, the middle panel is phosphoserine 727–STAT-3, and the bottom panel is immunoprecipitated STAT-3. As a positive control, STAT-3 was immunoprecipitated from whole-cell lysates from IL-6–stimulated AML12 hepatocytes (10 ng/ml, 15 minutes) and is shown on the right. Molecular-weight markers are shown on the left in kilodaltons. (b) DNA-binding ability of nuclear STAT-3 was analyzed by electrophoretic mobility-shift assay (EMSA) as described in Methods. Data from duplicate mice are shown. (c) DNA-binding ability of nuclear STAT-3 was compared with nuclear STAT-1 and STAT–5 DNA-binding activity. Control (C), 1-, 2-, and 3-hour time points were analyzed by EMSA as described in Methods. (d) Supershift analysis of STAT-3 and STAT-1 DNA-binding activity. Nuclear extracts from HepG2 cells stimulated with IL-6 (10 ng/ml) for 15 minutes are shown as an example of STAT-3 homodimers (S3:3), STAT-1:STAT-3 heterodimers (S1:3), and STAT-1 homodimers (S1:1). Ab-DNA-protein complexes are indicated by an asterisk. Control (C), 2-hour sham-operated, and 3-hour PH surgical time points were analyzed.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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