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, Gregory James Gores

Research output: Contribution to journalArticle

173 Citations (Scopus)

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
StatePublished - 2001

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Cathepsin B
Knockout Mice
Hepatocytes
Tumor Necrosis Factor-alpha
Apoptosis
Liver
Wounds and Injuries
Cats
Therapeutics
Cytochromes c
Ethylene Oxide
Injections
Caspase 9
Caspases
Proline
Adenoviridae
Caspase 3
Pharmacology

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Cathepsin B knockout mice are resistant to tumor necrosis factor-α-mediated hepatocyte apoptosis and liver injury : Implications for therapeutic applications. / Guicciardi, M. E.; Miyoshi, H.; Bronk, S. F.; Gores, Gregory James.

In: American Journal of Pathology, Vol. 159, No. 6, 2001, p. 2045-2054.

Research output: Contribution to journalArticle

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