Interleukin-5 inhibits translocation of Bax to the mitochondria, cytochrome c release, and activation of caspases in human eosinophils

The apoptosis and subsequent clearance of eosinophils without histotoxic me diator release is thought to be crucial in the resolution of airway inflamm ation in asthma. Interleukin-5 (IL-5) is a potent suppressor of eosinophil apoptosis. The mechanism by which IL-5 inhibits spontaneous eosinophil apop tosis was investigated. Freshly isolated eosinophils constitutively express ed the conformationally active form of Bax in the cytosol and nucleus. Duri ng spontaneous and staurosporine-induced apoptosis, Bax underwent a caspase -independent translocation to the mitochondria, which was inhibited by IL-5 . Eosinophil apoptosis was associated with the release of cytochrome c from the mitochondria, which was also inhibited by IL-5. IL-5 and the cell-perm eable caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-(OMe) fluoromethyl k etone (z-VAD.fmk), prevented phosphatidylserine (PS) externalization, altho ugh only IL-5 inhibited loss of mitochondrial membrane potential (Delta psi m). Peripheral blood eosinophils endogenously expressed "initiator" caspase -8 and -9. and "effector" caspase-3,-6, and -7. Spontaneous eosinophil apop tosis was associated with processing of caspase-3, -6, -7, -8, and -9. IL-5 and z-VAD.fmk prevented caspase activation in spontaneous apoptosis. The r esults suggest that spontaneous eosinophil apoptosis involves Bax transloca tion to the mitochondria, cytochrome c release, caspase-independent perturb ation of the mitochondrial membrane, and subsequent activation of caspases. IL-5 inhibits spontaneous eosinophil apoptosis at a site upstream of Bax t ranslocation. (C) 2001 by The American Society of Hematology.