Multiple Roles of IL6 in Hepatic Injury, Steatosis, and Senescence Aggregate to Suppress Tumorigenesis
Anat Shriki, Tali Lanton, Amir Sonnenblick, Orr Levkovitch‐Siany, Dana Eidelshtein, Rinat Abramovitch, Nofar Rosenberg, Orit Pappo, Sharona Elgavish, Yuval Nevo, Rifaat Safadi, Amnon Peled, Stefan Rose‐John, Eithan Galun, Jonathan H. Axelrod
Abstract
Abstract Hepatocellular carcinoma (HCC) typically develops on a background of chronic hepatitis for which the proinflammatory cytokine IL6 is conventionally considered a crucial driving factor. Paradoxically, IL6 also acts as a hepatoprotective factor in chronic liver injury. Here we used the multidrug-resistant gene 2 knockout (Mdr2−/−) mouse model to elucidate potential roles of IL6 in chronic hepatitis–associated liver cancer. Long-term analysis of three separate IL6/Stat3 signaling–deficient Mdr2−/− strains revealed aggravated liver injury with increased dysplastic nodule formation and significantly accelerated tumorigenesis in all strains. Tumorigenesis in the IL6/Stat3-perturbed models was strongly associated with enhanced macrophage accumulation and hepatosteatosis, phenotypes of nonalcoholic steatohepatitis (NASH), as well as with significant reductions in senescence and the senescence-associated secretory phenotype (SASP) accompanied by increased hepatocyte proliferation. These findings reveal a crucial suppressive role for IL6/Stat3 signaling in chronic hepatitis–associated hepatocarcinogenesis by impeding protumorigenic NASH-associated phenotypes and by reinforcing the antitumorigenic effects of the SASP. Significance: These findings describe a context-dependent role of IL6 signaling in hepatocarcinogenesis and predict that increased IL6-neutralizing sgp130 levels in some patients with NASH may herald early HCC development. See related commentary by Huynh and Ernst, p. 4671