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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
2009-01-16
IMMUNITY
Journal Article
30
1
56-66
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.
CELL PRESS
BAX-DEPENDENT APOPTOSIS; INDUCED LIVER-INJURY; DEFICIENT MICE; IN-VIVO; DEATH RECEPTORS; CELL-DEATH; T-CELLS; ACTIVATION; BCL-2; FAMILY
10.1016/j.immuni.2008.10.017
Refer to copyright notice on published article.

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