The role of TNF and Fas dependent signaling in animal models of inflammatory liver injury and liver cancer.

Tumor Necrosis Factor (TNF) alpha is a pleiotropic cytokine triggering either pro-inflammatory effects via NF-κB related pathways or apoptosis through activation of caspase-8. The related death ligands Fas and TRAIL use homologous receptors and similar signaling cascades but predominantly induce apoptosis. Here, we summarize our experimental approaches to analyze the mechanisms and consequences of TNF and Fas signaling with the ultimate aim to define molecular targets for the treatment of inflammatory liver disease and liver cancer. By using conditional knockout technology in mice we genetically dissected the I-kappa B kinase (IKK) complex consisting of IKK1/IKKα, IKK2/IKKβ and IKKγ/NEMO. We demonstrated that IKK2/IKKβ, but not IKKγ/NEMO might be a promising target for the prevention of liver injury after ischemia and reperfusion or treating steatohepatitis. Genetic inactivation of IKKγ/NEMO defined a new animal model of spontaneous hepatitis and hepatocarcinogenesis involving constitutive activation of caspase-8 and basal apoptosis. We further show that caspase-8 is not only regulated by post-translational modifications as suggested earlier, but also by complex transcriptional regulation. Targeted stimulation of the caspase-8 promoter by interferons alpha and gamma, cytotoxic drugs or p53 can substantially sensitize hepatoma cells for apoptosis, whereas hepatocellular carcinoma frequently present an inactive caspase-8 gene promoter. In conclusion, our work demonstrates that therapeutic intervention in the TNF-NF-κB-caspase-8 network is technically feasible and could be of potential benefit in inflammatory liver disease.