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

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

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160 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)860-9
Number of pages10
JournalJournal of Clinical Investigation
Volume115
Issue number4
DOIs
Publication statusPublished - Apr 2005

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

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