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

Klein, Christian, Wüstefeld, Torsten, Assmus, Ulrike, Roskams, Tania, Rose-John, Stefan, Müller, Michael, Manns, Michael P, Ernst, Mattias and Trautwein, Christian (2005) The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury. Journal of Clinical Investigation, 115 (4). pp. 860-9. ISSN 0021-9738

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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-alpha) 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.

Item Type: Article
Uncontrolled Keywords: animals,antigens, cd,concanavalin a,cytokine receptor gp130,dna-binding proteins,enzyme activation,extracellular signal-regulated map kinases,gene expression profiling,hepatitis,hepatocytes,interferon-gamma,interleukin-6,liver,male,membrane glycoproteins,mice,mice, inbred balb c,mice, knockout,stat1 transcription factor,stat3 transcription factor,serum amyloid a protein,signal transduction,t-lymphocytes,trans-activators,tumor necrosis factor-alpha
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Pure Connector
Date Deposited: 07 Jul 2014 12:04
Last Modified: 21 Apr 2020 22:53
URI: https://ueaeprints.uea.ac.uk/id/eprint/47737
DOI: 10.1172/JCI23640

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