Cathepsin B knockout mice are resistant to tumor necrosis factor-α-mediated hepatocyte apoptosis and liver injury: Implications for therapeutic applications

M. E. Guicciardi, H. Miyoshi, S. F. Bronk, G. J. Gores

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176 Scopus citations

Abstract

Tumor necrosis factor-α (TNF-α) contributes to liver injury by inducing hepatocyte apoptosis. Recent evidence suggests that cathepsin B (cat B) contributes to TNF-α-induced apoptosis in vitro. The aim of the present study was to determine whether cat B contributes to TNF-α-induced hepatocyte apoptosis and liver injury in vivo. Cat B knockout (catB-/-) and wild-type (catB+/+) mice were first infected with the adenovirus Ad5IkB expressing the Ikb superrepressor to inhibit nuclear factor-kB-induced survival signals and then treated with murine recombinant TNF-α. 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-α. 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-α 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-α-induced liver damage. The present data demonstrate that a cat B-mitochondrial apoptotic pathway plays a pivotal role in TNF-α-induced hepatocyte apoptosis and liver injury.

Original languageEnglish (US)
Pages (from-to)2045-2054
Number of pages10
JournalAmerican Journal of Pathology
Volume159
Issue number6
DOIs
StatePublished - 2001

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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