Differential protection with inhibitors of caspase-8 and caspase-3 in murine models of tumor necrosis factor and Fas receptor-mediated hepatocellularapoptosis

Excessive apoptosis has been implicated in a number of acute and chronic hu man diseases. The activation of caspases has been shown to be critical for the apoptotic process. The objective of this investigation was to evaluate the beneficial effects and mechanism of action of the caspase-8 inhibitor I ETD-CHO and the caspase-3 inhibitor DEVD-CHO against tumor necrosis factor (TNF)-induced hepatocellular apoptosis in vivo and compare these results to effects of the same inhibitors against Fas-induced apoptosis. Treatment of C3Heb/FeJ mice with 700 mg/kg galactosamine/100 mug/kg endotoxin induced p arenchymal apoptosis (indicated by caspase-3 activation and morphology) and severe liver injury (indicated by the increase in plasma alanine aminotran sferase activities and histology) at 7 h. Treatment with IETD-CHO or DEVD-C HO (10 mg/kg at 3, 4.5, and 5.5 h) significantly attenuated caspase-3 activ ation and liver injury. Western analysis showed that DEVD-CHO had no effect while IETD-CHO substantially reduced procaspase-3 and procaspase-9 process ing. On the other hand, caspase-3 activation and liver injury by the anti-F as antibody Jo-2 was completely prevented by a single dose of DEVD-CHO and, as previously shown, by IETD-CHO at 90 min. Both inhibitors prevented proc aspase-3 and procaspase-9 processing. Thus, there are fundamental differenc es in the efficacy of caspase inhibitors in these two models. We conclude t hat Fas may rely exclusively on caspase-8 activation and mitochondria to ac tivate caspase-3, which can process more procaspase-8 and thus propagate th e amplification of the apoptotic signal. TNF can activate a similar signali ng pathway. However, alternative signaling mechanisms seem to exist, which can compensate if the main pathway is blocked. (C) 2001 Academic Press.