Toxicological Sciences 58, 109-117 (2000)
Copyright © 2000 by the Society of Toxicology
Molecular and Genetic Toxicology |
Protection against Fas Receptor–Mediated Apoptosis in Hepatocytes and Nonparenchymal Cells by a Caspase-8 Inhibitor in Vivo: Evidence for a Postmitochondrial Processing of Caspase-8
,1
* Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205;
Department of Pharmacology and
Department of Preclinical Toxicology, Pharmacia & Upjohn, Inc., Kalamazoo, Michigan 49007
Lymphocytes can kill target cells including hepatocytes during various inflammatory diseases by Fas receptor–mediated apoptosis. Caspase-8 is activated at the receptor level, thereby initiating the processing of downstream effector caspases. The aim of this study was to investigate the time course of caspase-8 activation and to evaluate the efficacy of the caspase-8 inhibitor IETD-CHO in a model of Fas-induced apoptosis in vivo. C3Heb/FeJ mice were treated with the anti-Fas antibody Jo-2 (0.6 mg/kg). Western blot analysis demonstrated increased cytochrome c in the cytosol (20 min), which was followed by the progressive activation of caspase-3, -9 (40–120 min), and caspase-8 (120 min). At 90 and 120 min, extensive hemorrhage was observed, indicating damage to sinusoidal lining cells. In addition, high plasma ALT levels (997 ± 316 U/L) and histological evaluation indicated severe parenchymal cell injury. Parenchymal and nonparenchymal cells showed a similar increase in caspase-3 activity and DNA fragmentation. Treatment with IETD-CHO (10 mg/kg) attenuated the increase in caspase-3 activity and DNA fragmentation by 80–90% and completely prevented hemorrhage and parenchymal cell damage. IETD-CHO also prevented the early release of mitochondrial cytochrome c and the processing of caspase-3, -8, and -9. Thus, our data support the hypothesis that Fas-mediated apoptosis is dependent on caspase-8 activation in hepatocytes and nonparenchymal cells. However, the bulk of procaspase-8 is processed late, suggesting that only a small amount of procaspase-8 may actually be activated at the Fas receptor. This initial signal may be amplified by further activation of caspase-8 by effector caspases, i.e., after mitochondrial activation. Caspase-8 is a promising therapeutic target for inhibition of Fas-mediated apoptosis.
Key Words: liver cell apoptosis; Fas-induced liver failure; caspase cascade; mitochondria; cytochrome c; IETD-CHO; caspase-8 inhibitor.
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