Mechanisms of liver disease: cross-talk between the NF-κB and JNK pathways

The liver plays a central role in the transformation and degradation of endogenous and exogenous chemicals, and in the removal of unwanted cells such as damaged, genetically mutated and virus-infected cells. Because of this function, the liver is susceptible to toxicity caused by the products generated during these natural occurrences. Hepatocyte death is the major feature of liver injury. In response to liver injury, specific intracellular processes are initiated to maintain liver integrity. Inflammatory cytokines including tumor necrosis factor (TNF)alpha and interleukin-6 (IL-6) are key mediators of these processes and activate different cellular response such as proliferation, survival and death. TNF alpha induces specific signaling pathways in hepatocytes that lead to activation of either pro-survival mediators or effectors of cell death. Whereas activation of transcription factor NF-kappa B promotes survival, c-Jun N-terminal kinases (JNKs) and caspases are strategic effectors of cell death in the TNF alpha-mediated signaling pathway. This review summarizes recent advances in the mechanisms of TNF alpha-induced hepatotoxicity and suggests that NF-kappa B plays a protective role against JNK-induced hepatocyte death. Identification of the mechanisms regulating interplay between the NF-kappa B and JNK pathways is required in the search for novel targets for the treatment of liver disease, including hepatitis and hepatocellular carcinoma.