Antiapoptotic Effect of c-Jun N-terminal Kinase-1 through Mcl-1 Stabilization in TNF-Induced Hepatocyte Apoptosis

Background & Aimsc-Jun N-terminal Kinase (JNK) is a key regulator in tumor necrosis factor (TNF)–mediated liver injury. However, distinct roles for JNK1 and JNK2 in hepatocyte apoptosis are still unresolved. Although myeloid cell leukemia-1 (Mcl-1) has been reported as a substrate of JNK, the role of Mcl-1 and its functional regulation by JNK in TNF-induced hepatocyte apoptosis and liver injury remain to be elucidated.MethodsTNF-induced hepatocyte apoptosis was investigated in wild-type, jnk1−/− and jnk2−/− mice in vitro and in the galactosamine/TNF (GalN/TNF) liver injury model. For further analysis, we used adenoviruses expressing wild-type Mcl-1 or its substitution mutant, and the Cre/loxP system (mcl-1f/f) to delete mcl-1.Resultsjnk2−/− Hepatocytes showed increased Mcl-1 expression and were more resistant to TNF-induced apoptosis compared with wild-type or jnk1−/− hepatocytes. Increased Mcl-1 expression in jnk2−/− hepatocytes correlated with their JNK activity, which is mediated by residual JNK1 and higher than in wild-type or jnk1−/− hepatocytes. JNK activation led to phosphorylation of Mcl-1 in hepatocytes, and this increased the half-life of the Mcl-1 protein. Overexpression of Mcl-1 confirmed its antiapoptotic effect in TNF-induced hepatocyte apoptosis in vitro and in vivo. Deletion of mcl-1 in jnk2−/− hepatocytes increased TNF-induced hepatocyte apoptosis both in vitro and in GalN/TNF-induced liver injury model.Conclusionsjnk2−/− Hepatocytes are resistant to TNF-induced apoptosis. Activated JNK1 contributes to this antiapoptotic phenotype of jnk2−/− hepatocytes through phosphorylation-mediated stabilization of Mcl-1.