Fatal Hepatitis Mediated by Tumor Necrosis Factor TNF alpha Requires Caspase-8 and Involves the BH3-Only Proteins Bid and Bim

Kaufmann, T; Jost, PJ; Pellegrini, M; Puthalakath, H; Gugasyan, R; Gerondakis, S; Cretney, E; Smyth, MJ; Silke, J; Hakem, R; Bouillet, P; Mak, TW; Dixit, VM; Strasser, A

Author(s): Kaufmann, T; Jost, PJ; Pellegrini, M; Puthalakath, H; Gugasyan, R; Gerondakis, S; Cretney, E; Smyth, MJ; Silke, J; Hakem, R; Bouillet, P; Mak, TW; Dixit, VM; Strasser, A;
Details: Publication Year 2009-01-16,Volume 30,Issue #1,Page 56-66
Journal Title: IMMUNITY
Publication Type: Journal Article
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 TNF alpha. Injection with lipopolysaccharide (LPS) plus the transcriptional inhibitor D(+)-galactosamine (GaIN) or mitogenic T cell activation causes fatal hepatocyte apoptosis in mice, which is mediated by TNF alpha, 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+GaIN-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.
Publisher: CELL PRESS
Keywords: BAX-DEPENDENT APOPTOSIS; INDUCED LIVER-INJURY; DEFICIENT MICE; IN-VIVO; DEATH RECEPTORS; CELL-DEATH; T-CELLS; ACTIVATION; BCL-2; FAMILY
Publisher's Version: https://doi.org/10.1016/j.immuni.2008.10.017
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2009-01-16 12:00:00