Fatal Hepatitis Mediated by Tumor Necrosis Factor TNFα Requires Caspase-8 and Involves the BH3-Only Proteins Bid and Bim Academic Article uri icon

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.

authors

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

publication date

  • January 2009