The IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury.
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.
Klein
Christian
C
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. klein.christian@mh-hannover.de
Wüstefeld
Torsten
T
Assmus
Ulrike
U
Roskams
Tania
T
Rose-John
Stefan
S
Müller
Michael
M
Manns
Michael P
MP
Ernst
Mattias
M
Trautwein
Christian
C
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D003208:Concanavalin A / Q000633:toxicity; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020869:Gene Expression Profiling; D006505:Hepatitis / Q000276:immunology; D022781:Hepatocytes / Q000502:physiology*; D007371:Interferon-gamma / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D000685:Serum Amyloid A Protein / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015703:Antigens, CD; D004268:DNA-Binding Proteins; C494200:Il6st protein, mouse; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C489995:Saa2 protein, mouse; D000685:Serum Amyloid A Protein; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D050822:Cytokine Receptor gp130; D007371:Interferon-gamma; D048049:Extracellular Signal-Regulated MAP Kinases