Itraconazole antagonizes store-operated influx of calcium into chemoattractant-activated human neutrophils

Abstract

SUMMARY We have investigated the effects of itraconazole (0·1–10 µm), an antimycotic which is often used prophylactically in primary and secondary immunodeficiency disorders, including chronic granulomatous disease, on mobilization of Ca2+ and restoration of Ca2+ homeostasis following activation of neutrophils with FMLP or PAF. Transmembrane fluxes of Ca2+, as well as cytosolic concentrations of the cation were measured using a combination of spectrofluorimetric and radiometric procedures. The abruptly occurring increases in cytosolic Ca2+ following activation of the cells with either FMLP (1 µm) or PAF (200 nm) were unaffected by itraconazole. However, the subsequent store-operated influx of the cation was attenuated by itraconazole at concentrations of 0·25 µm and higher. The itraconazole-mediated inhibition of uptake of Ca2+ was not associated with detectable alterations in the intracellular concentrations of cyclic AMP, ATP or inositol triphosphate, and appeared to be compatible with antagonism of store-operated Ca2+ channels. Although a secondary property, this anti-inflammatory activity of itraconazole, if operative in vivo, may be beneficial in conditions associated with dysregulation of neutrophil Ca2+ handling such as CGD.