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 mediator release is thought to be crucial in the resolution of airway inflammation in asthma. Interleukin-5 (IL-5) is a potent suppressor of eosinophil apoptosis. The mechanism by which IL-5 inhibits spontaneous eosinophil apoptosis was investigated. Freshly isolated eosinophils constitutively expressed the conformationally active form of Bax in the cytosol and nucleus. During 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-permeable caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-(OMe) fluoromethyl ketone (z-VAD.fmk), prevented phosphatidylserine (PS) externalization, although only IL-5 inhibited loss of mitochondrial membrane potential (DeltaPsim). Peripheral blood eosinophils endogenously expressed "initiator" caspase-8 and -9, and "effector" caspase-3, -6, and -7. Spontaneous eosinophil apoptosis 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 results suggest that spontaneous eosinophil apoptosis involves Bax translocation to the mitochondria, cytochrome c release, caspase-independent perturbation of the mitochondrial membrane, and subsequent activation of caspases. IL-5 inhibits spontaneous eosinophil apoptosis at a site upstream of Bax translocation.