Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 159, Issue 6, Pages 2045-2054Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/S0002-9440(10)63056-8
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Funding
- NIDDK NIH HHS [DK 41876, R01 DK041876, R37 DK041876] Funding Source: Medline
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Tumor necrosis factor-alpha (TNF-alpha) contributes to liver injury by inducing hepatocyte apoptosis. Recent evidence suggests that cathepsin B (cat B) contributes to TNF-alpha -induced apoptosis in vitro. The aim of the present study was to determine whether cat B contributes to TNF-alpha -induced hepatocyte apoptosis and liver injury in vivo. Cat B knockout (catB(-/-)) and wild-type (catB(+/+)) mice were first Infected with the adenovirus Ad5I kappaB expressing the I kappaB superrepressor to inhibit nuclear factor-kappaB-induced survival signals and then treated with murine recombinant TNF-alpha. 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-alpha. 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-alpha 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-alpha -nduced liver damage. The present data demonstrate that a cat B-mitochondrial apoptotic pathway plays a pivotal role in TNF-alpha -induced hepatocyte apoptosis and liver injury.
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