Effects of rapamycin, cyclosporin A, and dexamethasone on interleukin 5-induced eosinophil degranulation and prolonged survival.

Abstract

Interleukin-5 (IL-5) enhances eosinophil degranulation and prolongs eosinophil survival. Rapamycin, cyclosporin A, and dexamethasone have been shown to influence either cytokine transcription, cytokine-mediated signalling, or degranulation by granulocytes. The study aimed to determine whether these agents inhibited IL-5-enhanced eosinophil survival or degranulation. Peripheral blood eosinophils were isolated from atopic subjects. The effects of serial dilutions (10(-6)-10(-9) M) of these drugs or vehicle control on 1) the viability of eosinophils cultured (1-5 days) in the presence and absence of recombinant human IL-5, as measured by propidium iodide staining and flow cytometry, and 2) degranulation of eosinophils preincubated (45 min) with rhIL-5 or medium control, as measured by eosinophil cationic protein (ECP) release after stimulation with serum-coated Sephadex beads, were assessed. Dexamethasone and rapamycin produced significant, concentration-dependent inhibition of IL-5-enhanced eosinophil survival at pharmacologic concentrations, whereas cyclosporin A did not. Prior incubation of eosinophils with IL-5, as compared with medium control, significantly enhanced ECP release by eosinophils on subsequent exposure to serum-coated Sephadex beads. Cyclosporin A and rapamycin significantly inhibited IL-5-enhanced ECP release in a concentration-dependent fashion, whereas dexamethasone did not. All three drugs had no significant effect on eosinophil survival and degranulation in the absence of IL-5. Our results suggest that immunosuppressive drugs may inhibit IL-5-mediated mechanisms in eosinophils which result in enhanced survival and release of granule contents. These findings may be relevant to the further development of therapeutic strategies in allergic diseases.