Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 106, Issue 9, Pages 1127-1137Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI9914
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Funding
- NCI NIH HHS [R01 CA069008, CA69008] Funding Source: Medline
- NIDDK NIH HHS [DK 41876, R01 DK041876, R37 DK041876] Funding Source: Medline
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TNF-alpha -induced apoptosis is thought to involve mediators from acidic vesicles. Cathepsin B (cat B), a lysosomal cysteine protease, has recently been implicated in apoptosis. To determine whether cat B contributes to TNF-alpha -induced apoptosis, we exposed mouse hepatocytes to the cytokine in vitro and in vivo. Isolated hepatocytes treated with TNF-alpha in the presence of the transcription inhibitor actinomycin D (AcD) accumulated cat B in their cytosol. Further experiments using cell-free systems indicated that caspase-8 caused release of active cat B from purified lysosomes and that cat B, in turn, increased cytosol-induced release of cytochrome c from mitochondria. Consistent with these observations, the ability of TNF-alpha /AcD to induce mitochondrial release of cytochrome c, caspase activation, and apoptosis of isolated hepatocytes was markedly diminished in cells from CatB(-/-) mice. Deletion of the CatB gene resulted in diminished Liver injury and enhanced survival after treatment in vivo with TNF-alpha and an adenovirus construct expressing the I kappaB superrepressor. Collectively, these observations suggest that caspase-mediated release of cat B from lysosomes enhances mitochondrial release of cytochrome c and subsequent caspase activation in TNF-alpha -treated hepatocytes.
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