| First Author | Guicciardi ME | Year | 2001 |
| Journal | Am J Pathol | Volume | 159 |
| Issue | 6 | Pages | 2045-54 |
| PubMed ID | 11733355 | Mgi Jnum | J:72935 |
| Mgi Id | MGI:2154017 | Doi | 10.1016/s0002-9440(10)63056-8 |
| Citation | Guicciardi ME, et al. (2001) Cathepsin B Knockout Mice Are Resistant to Tumor Necrosis Factor-alpha-Mediated Hepatocyte Apoptosis and Liver Injury : Implications for Therapeutic Applications. Am J Pathol 159(6):2045-54 |
| abstractText | 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 Ad5IkappaB expressing the IkappaB 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-induced 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. |
