Obesity is a constantly increasing health burden affecting more than 30% of the population of westernized countries. In addition to classical associated disorders, obesity was also previously reported to increase the incidence of hepatocellular carcinoma (HCC) development, in part through activation of obesity-associated pro-inflammatory signaling and the release of inflammatory cytokines such as TNFα and IL-6, both known as tumor-promoting cytokines. Nevertheless, how these inflammatory cytokines trigger HCC development is currently not fully un- derstood.
The current work reports that abrogation of IL-6Rα signaling in lean mice pro- tects against DEN-induced HCC development. This HCC protection occurs via destabilization of anti-apoptotic Bcl-2 family member Mcl-1, thus promoting hep- atocyte apoptosis. In lean mice IL-6 regulates the stability of Mcl-1 via inhibi- tion of PP-1α expression which promotes GSK-3β inactivation by serine 9 residue phosphorylation. In addition, IL-6 suppresses expression of the Mcl-1 E3 ligase Mule. Consequently, IL-6Rα deficiency activates PP1-α and Mule expression re- sulting in increased Mcl-1 turnover and protection against HCC development. In contrast, in obese mice inhibition of PP1-α and Mule expression leading to Mcl-1 stabilization occurs independent from IL-6 signaling.
Furthermore, the current work could demonstrate that IL-6Rα signaling in T cells is essential for the development of HCC indicated by the protective effect of IL-6Rα deficiency on T cells.
Collectively, this study provides evidence that IL-6 and obesity inhibit hepato- cyte apoptosis through Mcl-1 stabilization thus promoting liver carcinogenesis
