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(Journal of Leukocyte Biology. 2001;70:767-775.)
© 2001 by Society for Leukocyte Biology

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

Séverine Létuvé^*, Anne Druilhe^*, Martine Grandsaigne^*, Michel Aubier^*, and Marina Pretolani^*

^* Institut National de la Santé et de la Recherche Médicale U408, Faculté de Médecine Xavier Bichat, and
Service de Pneumologie, Hôpital Bichat, Paris, France

Correspondence: Marina Pretolani, Ph.D., INSERM U408, Faculté de Médecine Xavier Bichat, 16, rue Henri Huchard, 75018 Paris, France. E-mail: mpretol{at}bichat.inserm.fr

In this study, we examined the relative importance of caspases and mitochondria 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 (_m) and with caspase-8 and caspase-3 activation. Interleukin (IL)-5 and interferon (IFN)-, two cytokines known to prolong eosinophil survival, inhibited Fas-mediated apoptosis and caspase activation but poorly affected the decrease in _m. Eosinophil incubation with bongkrekic acid, an inhibitor of the mitochondrial permeability transition pore (MPTP) opening, failed to modify Fas-mediated loss in _m, caspase activation, and apoptosis. In contrast, caspase inhibitors markedly reduced eosinophil apoptosis without significantly affecting _m dissipation. We conclude that caspase-8 and caspase-3 activation, but not MPTP opening, mediate Fas-induced eosinophil apoptosis and are the main targets for the protective effect of IL-5 and IFN-.

Key Words: cell death • asthma • granulocytes • _m

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