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

Abstract

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 Ca 2+ handling such as CGD.