| First Author | Guicciardi ME | Year | 2000 |
| Journal | J Clin Invest | Volume | 106 |
| Issue | 9 | Pages | 1127-37 |
| PubMed ID | 11067865 | Mgi Jnum | J:77596 |
| Mgi Id | MGI:2182071 | Doi | 10.1172/JCI9914 |
| Citation | Guicciardi ME, et al. (2000) Cathepsin B contributes to TNF-alpha-mediated hepatocyte apoptosis by promoting mitochondrial release of cytochrome c. J Clin Invest 106(9):1127-37 |
| abstractText | 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 IkappaB 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. |
