The Mitochondrial Permeability Transition Augments Fas-induced Apoptosis in Mouse Hepatocytes*

Tumor necrosis factor-α receptor 1 and Fas recruit overlapping signaling pathways. To clarify the differences between tumor necrosis factor α (TNFα) and Fas pathways in hepatocyte apoptosis, primary mouse hepatocytes were treated with TNFα or an agonist anti-Fas antibody after infection with an adenovirus expressing an IκB superrepressor (Ad5IκB). Treatment with TNFα induced apoptosis in Ad5IκB-infected mouse hepatocytes, as we previously reported for rat hepatocytes. Ad5IκB plus anti-Fas antibody or actinomycin D plus anti-Fas antibody rapidly induced apoptosis, whereas anti-Fas antibody alone produced little cytotoxicity. The proteasome inhibitor (MG-132) and a dominant-negative mutant of nuclear factor-κB-inducing kinase also promoted TNFα- and Fas-mediated apoptosis. Expression of either crmA or a dominant-negative mutant of the Fas-associated death domain protein prevented TNFα- and Fas-mediated apoptosis. In addition, the caspase inhibitors, DEVD-cho and IETD-fmk, inhibited TNFα- and Fas-mediated apoptosis. In Ad5IκB-infected hepatocytes, caspases-3 and -8 were activated within 2 h after treatment with anti-Fas antibody or within 6 h after TNFα treatment. Confocal microscopy demonstrated onset of the mitochondrial permeability transition (MPT) and mitochondrial depolarization by 2–3 h after anti-Fas antibody treatment and 8–10 h after TNFα treatment, followed by cytochromec release. The combination of the MPT inhibitors, cyclosporin A, and trifluoperazine, protected Ad5IκB-infected hepatocytes from TNFα-mediated apoptosis. After anti-Fas antibody, cyclosporin A and trifluoperazine decreased cytochrome crelease but did not prevent caspase-3 activation and cell-death. In conclusion, nuclear factor-κB activation protects mouse hepatocytes against both TNFα- and Fas-mediated apoptosis. TNFα and Fas recruit similar but nonidentical, pathways signaling apoptosis. The MPT is obligatory for TNFα-induced apoptosis. In Fas-mediated apoptosis, the MPT accelerates the apoptogenic events but is not obligatory for them.

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