Hematopoietic cells-derived Jnk1 drives hepatic injury and hepatocellular carcinoma in IKKγ/NEMO-deleted livers

Background & Aims: Currently the focus of future targeted therapy is to define novel pathways involved in the promotion of the survival and/or death of transformed hepatocytes and the control of their progression into HCC. Of particular interest is the interaction between mechanisms controlling NEMO, the regulatory subunit of NF-κB, and Jnk activation for directing cell death and survival. In the present study, we aimed to define the relevance of Jnk in hepatocyte-specific NEMO knockout mice (NEMOΔhepa), a genetic model of chronic inflammatory liver injury. Methods: We generated global Jnk1-/-/NEMOΔhepa and Jnk2-/-/NEMOΔhepa and mice with dual conditional deletion of Jnk1 and NEMO in hepatocytes (DKOΔhepa) and studied the progression of liver disease. Moreover, we studied the expression of Jnk during acute liver injury, evaluated the role of Jnk1 in bone marrow-derived cells, and analyzed the expression of NEMO and pJnk in human diseased-livers. Results: Deletion of Jnk1 significantly aggravated the progression of liver disease, exacerbating apoptosis, compensatory proliferation and carcinogenesis in NEMOΔhepa mice. Jnk2-/-/NEMOΔhepa showed increased RIP-1 and RIP-3 expression and hepatic inflammation. Jnk1 in hematopoietic cells rather than hepatocytes had an impact on the progression of chronic liver disease in NEMOΔhepa livers. These findings are of clinical relevance since down-regulation of NEMO expression was observed in hepatocytes of patients with advanced liver disease whereas NEMO and pJnk were expressed in a large amount of infiltrating cells. Conclusions: While Jnk1 mediates protective effects in NEMOΔhepa mice, Jnk1 in hematopoietic cells rather than hepatocytes is a crucial driver of hepatic injury. Jnk2 function seems to be independent of Jnk1. These results elucidate the complex function of Jnk in chronic inflammatory liver disease.