The dominant role of CPP32 subfamily in fas-mediated hepatitis.
Fas is a cell surface molecule that transduces the apoptotic death signaling on the stimulation of Fas ligand, and plays the dominant role in various disease states. The lethal effect of Fas antibody in mice has been reported, and this experimental procedure has been used as the model for hepatitis. Recently, the prevention of this Fas antibody-induced hepatitis by the broad caspase inhibitor (z-VAD.fmk) has been reported. In the present study, we additionally demonstrated that the CPP32 subfamily, rather than the ICE subfamily, plays the dominant role in the Fas antibody-induced hepatitis. Fas antibody-injection induced chromosomal DNA fragmentation and CPP32 subfamily-activation in both the liver and lung. Tissue damage observed in the lung was weak as compared with liver damage. When mice were exposed to DEVD-CHO (specific inhibitor of CPP32 subfamily), this lethal effect of Fas antibody, tissue destruction, and CPP32 subfamily-activation were prevented. In contrast, YVAD-CHO (specific inhibitor of ICE subfamily) could not prevent the lethal effect of Fas antibody. We propose here that the CPP32 subfamily plays the dominant role in Fas-mediated hepatitis, and DEVD-CHO would be an effective cure for hepatitis.
Suzuki
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Drug Safety Research Laboratory, Daiichi Pharmaceutical Co., Ltd, Tokyo R&D Center, Japan. LEB00373@niftyserve.or.jp
D000818:Animals; D000906:Antibodies / Q000502:physiology; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases / Q000502:physiology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D053938:DNA Fragmentation; D004789:Enzyme Activation; D004792:Enzyme Precursors; D006505:Hepatitis / Q000209:etiology* / Q000473:pathology; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008168:Lung / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology*; D019014:fas Receptor / Q000276:immunology / Q000502:physiology*
D000906:Antibodies; D015853:Cysteine Proteinase Inhibitors; D004792:Enzyme Precursors; D009842:Oligopeptides; C108637:aspartyl-glutamyl-valyl-aspartal; D019014:fas Receptor; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases