title: Fatal hepatitis mediated by tumor necrosis factor TNFalpha requires caspase-8 and involves the BH3-only proteins Bid and Bim.
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.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kaufmann
authors.forename: Philipp J
authors.initials: PJ
authors.lastname: Jost
authors.forename: Marc
authors.initials: M
authors.lastname: Pellegrini
authors.forename: Hamsa
authors.initials: H
authors.lastname: Puthalakath
authors.forename: Raffi
authors.initials: R
authors.lastname: Gugasyan
authors.forename: Steve
authors.initials: S
authors.lastname: Gerondakis
authors.forename: Erika
authors.initials: E
authors.lastname: Cretney
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: John
authors.initials: J
authors.lastname: Silke
authors.forename: Razq
authors.initials: R
authors.lastname: Hakem
authors.forename: Philippe
authors.initials: P
authors.lastname: Bouillet
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Vishva M
authors.initials: VM
authors.lastname: Dixit
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D053181:Caspase 8 / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury; D022781:Hepatocytes / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C494815:Bid protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; D053181:Caspase 8