Interleukin 6/gp130‐dependent pathways are protective during chronic liver diseases

The contribution of the acute phase inducer interleukin 6 (IL‐6) in the pathogenesis of liver diseases is yet unclear. Our analysis showed enhanced expression of IL‐6 in livers derived from patients with acute and chronic liver diseases. Additionally, IL‐6 plasma levels were significantly increased in patients with chronic liver diseases and showed an inverse correlation with biochemical markers of liver function and a positive correlation with inflammatory markers, signs of portal hypertension, and the degree of liver fibrosis. To prove the relevance of these clinical findings, we applied the tetrachlorcarbonide (CCl4) model to conditional knockout animals (Cre/loxP system) for gp130, the common signal transducer of IL‐6 family cytokines. Cre recombinases were expressed through a hepatocyte (AlfpCre) and a ubiquitous (MxCre) control element. Gp130 deleted mice had a totally abolished STAT3 activation and acute phase response induction, but gp130 deletion had no effect on the degree of acute liver injury and subsequent hepatocyte proliferation. In contrast, during chronic liver injury induced by biweekly application of CCl4, deletion of the gp130 receptor in nonparenchymal liver cells and not hepatocytes resulted in fibrosis progression. In conclusion, our experiments indicate an involvement of IL‐6 in the pathogenesis of liver diseases and suggest a protective role of IL‐6/gp130‐dependent pathways in nonparenchymal liver cells during fibrosis progression in chronic liver diseases.

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