Fatal hepatitis mediated by tumor necrosis factor TNFalpha requires caspase-8 and involves the BH3-only proteins Bid and Bim.

Thomas Kaufmann, Philipp J Jost, Marc Pellegrini, Hamsa Puthalakath, Raffi Gugasyan, Steve Gerondakis, Erika Cretney, Mark J Smyth, John Silke, Razq Hakem, Philippe Bouillet, Tak W Mak, Vishva M Dixit, Andreas Strasser, Thomas Kaufmann, Philipp J. Jost, Marc Pellegrini, Hamsa Puthalakath, Raffi Gugasyan, Steve Gerondakis, Erika Cretney, Mark J. Smyth, John Silke, Razq Hakem, Philippe Bouillet, Tak W. Mak, Vishva M. Dixit, Andreas Strasser

Index: Immunity 30(1) , 56-66, (2009)

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Abstract

Apoptotic death of hepatocytes, a contributor to many chronic and acute liver diseases, can be a consequence of overactivation of the immune system and is often mediated by TNFalpha. Injection with lipopolysaccharide (LPS) plus the transcriptional inhibitor D(+)-galactosamine (GalN) or mitogenic T cell activation causes fatal hepatocyte apoptosis in mice, which is mediated by TNFalpha, but the effector mechanisms remain unclear. Our analysis of gene-targeted mice showed that caspase-8 is essential for hepatocyte killing in both settings. Loss of Bid, the proapoptotic BH3-only protein activated by caspase-8 and essential for Fas ligand-induced hepatocyte killing, resulted only in a minor reduction of liver damage. However, combined loss of Bid and another BH3-only protein, Bim, activated by c-Jun N-terminal kinase (JNK), protected mice from LPS+GalN-induced hepatitis. These observations identify caspase-8 and the BH3-only proteins Bid and Bim as potential therapeutic targets for treatment of inflammatory liver diseases.