Involvement of caspases and of mitochondria in Fas ligation-induced eosinophil apoptosis: modulation by interleukin-5 and interferon-gamma

In this study, we examined the relative importance of caspases and mitochon dria in Fas-mediated eosinophil apoptosis. Stimulation of human peripheral blood eosinophils with an agonistic anti-human Fas monoclonal antibody, but not with control IgM, induced a time-dependent increase in their apoptosis , which was associated with a loss in mitochondrial transmembrane potential and with caspase-8 and caspase-3 activation. Interleukin (IL)-5 and interf eron (IFN)-gamma, two cytokines known to prolong eosinophil survival, inhib ited Fas-mediated apoptosis and caspase activation but poorly affected the decrease in Delta Psi (m). Eosinophil incubation with bongkrekic acid, an i nhibitor of the mitochondrial permeability transition pore (MPTP) opening, failed to modify Fas-mediated loss in Delta Psi (m), caspase activation, an d apoptosis. In contrast, caspase inhibitors markedly reduced eosinophil ap optosis without significantly affecting Delta Psi (m), dissipation. We conc lude that caspase-8 and caspase-3 activation, but not MPTP opening, mediate Fas-induced eosinophil apoptosis and are the main targets for the protecti ve effect of IL-5 and IFN-gamma.