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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gp130 in hepatocytes is essential for IL-6–dependent protection in Con A...
gp130 in hepatocytes is essential for IL-6–dependent protection in Con A–induced hepatitis. Con A hepatitis was induced by intravenous injection of 32.5 mg/kg Con A in wild-type (gp130LoxP/LoxP) and hepatocyte-specific gp130-null (alfpCre gp130LoxP/LoxP) mice. Mice were pretreated for 3 hours with NaCl (solid line) or IL-6 (200 μg/kg) (dotted line) before i.v. injection of Con A. Liver injury was quantified by detection of AST. (A) Time course of AST serum levels during Con A–induced hepatitis in wild-type mice pretreated with NaCl (solid line) or IL-6 (dotted line). #P < 0.01 and *P < 0.05 vs. corresponding IL-6–pretreated wild-type control group at the same time point. (B) Time course of AST serum levels during Con A–induced hepatitis in alfpCre gp130LoxP/LoxP mice pretreated with NaCl (solid line) or IL-6 (dotted line).