Cathepsin B knockout mice are resistant to tumor necrosis factor-alpha-mediated hepatocyte apoptosis and liver injury: implications for therapeutic applications.
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 kappa B expressing the I kappa B superrepressor to inhibit nuclear factor-kappa B-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.
Guicciardi
M E
ME
Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic, and Foundation, Rochester, Minnesota 55905, USA.
Miyoshi
H
H
Bronk
S F
SF
Gores
G J
GJ
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D056486:Chemical and Drug Induced Liver Injury; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D004351:Drug Resistance; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D005838:Genotype; D022781:Hepatocytes / Q000187:drug effects*; D020672:I-kappa B Proteins / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008107:Liver Diseases / Q000235:genetics / Q000517:prevention & control; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D020672:I-kappa B Proteins; D014409:Tumor Necrosis Factor-alpha; C068250:N-(3-propylcarbamoyloxirane-2-carbonyl)-isoleucyl-proline; D002401:Cathepsin B