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Cathepsin B Knockout Mice Are Resistant to Tumor Necrosis Factor-{alpha}-Mediated Hepatocyte Apoptosis and Liver Injury : Implications for Therapeutic Applications

Cathepsin B Knockout Mice Are Resistant to Tumor Necrosis Factor-{alpha}-Mediated Hepatocyte Apoptosis and Liver Injury : Implications for Therapeutic Applications

Abstract

Tumor necrosis factor- (TNF- ) contributes to liver injury by inducing hepatocyte apoptosis. Recent evidence suggests that cathepsin B (cat B) contributes to TNF- -induced apoptosis in vitro . The aim of the present study was to determine whether cat B contributes to TNF- -induced hepatocyte apoptosis and liver injury in vivo . Cat B knockout ( catB -/- ) and wild-type ( catB +/+ ) mice were first infected with the adenovirus Ad5I B expressing the I B superrepressor to inhibit nuclear factor- B-induced survival signals and then treated with murine recombinant TNF- . Massive hepatocyte apoptosis with mitochondrial release of cytochrome c and activation of caspases 9 and 3 was detected in catB +/+ mice 2 hours after the injection of TNF- . In contrast, significantly less hepatocyte apoptosis and no detectable release of cytochrome c or caspase activation occurred in the livers of catB -/- mice. By 4 hours after TNF- injection, only 20% of the catB +/+ mice were alive as compared to 85% of catB -/- mice. Pharmacological inhibition of cat B in catB +/+ mice with L -3-trans-(propylcarbamoyl)oxirane-2-carbonyl- L -isoleucyl- L -proline (CA-074 Me) also reduced TNF- -induced liver damage. The present data demonstrate that a cat B-mitochondrial apoptotic pathway plays a pivotal role in TNF- -induced hepatocyte apoptosis and liver injury.
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