The IL-6–gp130–STAT3 pathway in hepatocytes triggers liver protection in T cell–mediated liver injury
Christian Klein, … , Mattias Ernst, Christian Trautwein
Christian Klein, … , Mattias Ernst, Christian Trautwein
Published April 1, 2005
Citation Information: J Clin Invest. 2005;115(4):860-869. https://doi.org/10.1172/JCI23640.
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Article Hepatology

The IL-6–gp130–STAT3 pathway in hepatocytes triggers liver protection in T cell–mediated liver injury

Abstract

Increasing evidence demonstrates that IL-6 has a protective role during liver injury. IL-6 activates intracellular pathways via the gp130 receptor. In order to identify IL-6–gp130 pathways involved in mediating liver protection, we analyzed hepatocyte-specific gp130 knockout mice in a concanavalin A–induced (Con A–induced) model of immune-mediated hepatitis. We demonstrated that IL-6–gp130–dependent pathways in hepatocytes alone are sufficient for triggering protection in Con A–induced hepatitis. gp130-STAT3 signaling in hepatocytes mediates the IL-6–triggered protective effect. This was demonstrated by analysis of IL-6–induced protection in mice selectively deficient for gp130-dependent STAT1/3 or gp130-SHP2-RAS signaling in hepatocytes. To identify IL-6–gp130–STAT1/3 dependently expressed liver-protective factors, we performed gene array analysis of hepatic gene expression in hepatocyte-specific gp130–/– mice as well as in gp130-STAT1/3– and gp130-SHP2-RAS-MAPK–deficient mice. The mouse IL-8 ortholog KC (also known as Gro-α) and serum amyloid A2 (SAA2) was identified as differentially IL-6–gp130–STAT3–regulated genes. Hepatic expression of KC and SAA2 mediate the liver-protective potential of IL-6, since treatment with recombinant KC or serum SAA2 effectively reduced liver injury during Con A–induced hepatitis. In summary, this study defines IL-6–gp130–STAT3–dependent gene expression in hepatocytes that mediates IL-6–triggered protection in immune-mediated Con A–induced hepatitis. Additionally, we identified the IL-6–gp130–STAT3–dependent proteins KC and SAA2 as new candidates for therapeutic targets in liver diseases.

Authors

Christian Klein, Torsten Wüstefeld, Ulrike Assmus, Tania Roskams, Stefan Rose-John, Michael Müller, Michael P. Manns, Mattias Ernst, Christian Trautwein

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Acute-phase protein SAA2 and the chemokine KC are IL-6–gp130–STAT–induce...
Acute-phase protein SAA2 and the chemokine KC are IL-6–gp130–STAT–induced, liver-protective proteins. (A) SAA2 serum levels after IL-6 (200 μg/kg) injection. Each time point represents the serum of 3–5 animals. Filled squares represent wild-type mice, open squares show alfpCre gp130LoxP/LoxP mice, filled triangles mark alfpCre gp130Y757F/LoxP mice, and open triangles represent alfpCre gp130ΔSTAT/LoxP. (B) Pretreatment with recombinant SAA (0.8 mg/kg) leads to a significant reduction of AST levels in the time course of Con A–induced hepatitis in wild-type mice. Either SAA (dotted line) or NaCl (solid line) was injected intravenously 1 hour before induction of Con A–induced hepatitis. (C) Serum KC levels after IL-6 injection. Filled squares represent wild-type mice, open squares show alfpCre gp130LoxP/LoxPmice, filled triangles mark alfpCre gp130Y757F/LoxP mice, and open triangles represent alfpCre gp130ΔSTAT/LoxP. (D) IL-6 treatment results in a significant reduction of PMN infiltration during Con A–induced hepatitis. Four hours after Con A injection, the influx of PMNs was counted on H&:E-stained paraffin sections by an experienced liver pathologist. The arrows mark liver infiltrating PMNs. hPF, high powered field. (E) KC (40 μg/kg) treatment leads to a significant reduction of AST levels during Con A–induced hepatitis. Eight mice per group were treated with either KC (dotted line) or NaCl (solid line) 1 hour before Con A injection. §P < 0.001 and *P < 0.05 vs. corresponding control groups at the same time point.