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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Generation and functional characterization of hepatocyte-specific gp130Δ...
Generation and functional characterization of hepatocyte-specific gp130ΔSTAT/LoxP and gp130Y757F/LoxP mice. (A) alfpCre gp130LoxP/LoxP mice were generated by breeding alfpCre mice with animals expressing LoxP-flanked gp130 alleles (25). Hepatocyte-specific gp130ΔSTAT/LoxP animals (alfpCre gp130ΔSTAT/LoxP) were generated by crossing alfpCre gp130LoxP/LoxP with gp130ΔSTAT/ΔSTAT mice, which express a truncated gp130 knockin allele encoding a truncated gp130 protein that lacks the domains mediating STAT1 and STAT3 activation (26). Hepatocyte-specific gp130Y757F/LoxP animals (alfpCre gp130Y757F/LoxP) were bred by crossing alfpCre gp130LoxP/LoxP with gp130Y757F/Y757F mice, which express a gp130 allele encoding a phenylalanine substitution of the Y757 residue (32), thereby rendering gp130 incapable of recruiting SHP2 and activating the RAS-MAPK pathway. Animals were genotyped by PCR analysis for alfpCre, gp130LoxP, and gp130Y757F alleles. (B and E) The functional characterization of hepatocyte-specific gp130 mutant mice. Gp130 downstream-signaling pathways were analyzed by monitoring of phosphorylated STAT3 and phosphorylated ERK2 (p42) expression in whole cell extracts of primary hepatocytes isolated from wild-type (B), alfpCre gp130LoxP/LoxP (C), alfpCre gp130Y757F/LoxP (D), or alfp Cre gp130ΔSTAT/LoxP mice (E). Activation of phosphorylated STAT1 was not detected in any of the 4 mouse strains.