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Am. J. Respir. Cell Mol. Biol., Volume 26, Number 5, May, 2002 565-571

Critical Role of Mitochondria, but Not Caspases, during Glucocorticosteroid-Induced Human Eosinophil Apoptosis

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

Glucocorticosteroids are potent anti-inflammatory drugs used in the treatment of eosinophilic disorders. These molecules directly promote eosinophil apoptosis, yet the molecular mechanisms regulating this process remain ill-defined. We show here that stimulation of human peripheral blood eosinophils with dexamethasone induced DNA fragmentation, chromatin and cytoplasm condensation, and caspase-3 activation, as assessed by the proteolysis of its zymogen form and by the increase of caspase-3-like activity in eosinophil lysates. These phenomena were accompanied by a reduced uptake of the mitochondrial potential-sensitive marker DiOC6(3), suggestive of mitochondrial membrane permeabilization. Eosinophil incubation with the caspase-3 inhibitor, Z-Asp-Glu-Val-Asp-fluromethylketone, or with the broad spectrum caspase inhibitor, Z-Val-Ala-Asp-fluromethylketone, inhibited caspase-3-like activity generation but failed to modify dexamethasone-mediated loss in mitochondrial transmembrane potential and eosinophil apoptosis. In contrast, bongkrekic acid, a ligand of the mitochondrial permeability transition pore component, adenine nucleotide translocator, prevented both dexamethasone-induced mitochondrial disruption and apoptosis. We conclude that the mitochondrial permeability transition pore, rather than the caspase cascade, plays a critical role in the propagation of glucocorticosteroid-mediated apoptotic signals in human eosinophils.

Abbreviations: apoptosis-inducing factor, AIF; amino-4-methyl coumarin, AMC; adenine nucleotide translocator, ANT; carbonyl cyanide m-chlorophenylhydrazone, CCCP; mitochondrial transmembrane potential, Delta Psi m; 3,3'-dihexyloxacarbocyanine iodide, DiOC6(3); dimethyl sulfoxide, DMSO; forward scatter, FS; interleukin, IL; monoclonal antibody, mAb; mitochondrial permeability transition pore, MPTP; optical density, OD; phosphate-buffered saline, PBS; processed caspase-3, p17; zymogen caspase-3, p32; side scatter, SS; Z-Asp-Glu-Val-Asp-fluromethylketone, Z-DEVD-fmk; Z-Val-Ala-Asp-fmk, Z-VAD-fmk.




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