title: Involvement of caspases and of mitochondria in Fas ligation-induced eosinophil apoptosis: modulation by interleukin-5 and interferon-gamma.
abstract: 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 (DeltaPsi(m)) and with caspase-8 and caspase-3 activation. Interleukin (IL)-5 and interferon (IFN)-gamma, two cytokines known to prolong eosinophil survival, inhibited Fas-mediated apoptosis and caspase activation but poorly affected the decrease in DeltaPsi(m). Eosinophil incubation with bongkrekic acid, an inhibitor of the mitochondrial permeability transition pore (MPTP) opening, failed to modify Fas-mediated loss in DeltaPsi(m), caspase activation, and apoptosis. In contrast, caspase inhibitors markedly reduced eosinophil apoptosis without significantly affecting DeltaPsi(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-gamma.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U408, Faculté de Médecine Xavier Bichat, Hôpital Bichat, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Létuvé
authors.forename: A
authors.initials: A
authors.lastname: Druilhe
authors.forename: M
authors.initials: M
authors.lastname: Grandsaigne
authors.forename: M
authors.initials: M
authors.lastname: Aubier
authors.forename: M
authors.initials: M
authors.lastname: Pretolani
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001865:Bongkrekic Acid / Q000494:pharmacology; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000502:physiology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D053222:Fas Ligand Protein; D006801:Humans; D017681:Hypereosinophilic Syndrome / Q000097:blood; D007075:Immunoglobulin M / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D015848:Interleukin-5 / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D007473:Ion Channels; D008562:Membrane Glycoproteins / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009842:Oligopeptides / Q000494:pharmacology; D011657:Pulmonary Eosinophilia / Q000276:immunology / Q000473:pathology; D011994:Recombinant Proteins / Q000494:pharmacology; D019014:fas Receptor / Q000276:immunology / Q000502:physiology*
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000911:Antibodies, Monoclonal; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D003574:Cytochrome c Group; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007075:Immunoglobulin M; D015848:Interleukin-5; D007473:Ion Channels; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009842:Oligopeptides; D011994:Recombinant Proteins; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C403753:benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019014:fas Receptor; D001865:Bongkrekic Acid; D007371:Interferon-gamma; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases