Itraconazole antagonizes store-operated influx of calcium into chemoattractant-activated human neutrophils.
We have investigated the effects of itraconazole (0.1-10 micro m), an antimycotic which is often used prophylactically in primary and secondary immunodeficiency disorders, including chronic granulomatous disease, on mobilization of Ca(2+) and restoration of Ca(2+) homeostasis following activation of neutrophils with FMLP or PAF. Transmembrane fluxes of Ca(2+), as well as cytosolic concentrations of the cation were measured using a combination of spectrofluorimetric and radiometric procedures. The abruptly occurring increases in cytosolic Ca(2+) following activation of the cells with either FMLP (1 micro m) 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 micro m and higher. The itraconazole-mediated inhibition of uptake of Ca(2+) 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 Ca(2+) 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.
Steel
H C
HC
Medical Research Council Unit for Inflammation and Immunity, Department of Immunology, Institute for Pathology, Faculty of Health Sciences, University of Pretoria, South Africa. hsteel@postillion.up.ac.za
Anderson
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D000935:Antifungal Agents / Q000494:pharmacology*; D001693:Biological Transport, Active; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects*; D002462:Cell Membrane / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000494:pharmacology; D013050:Spectrometry, Fluorescence
D000935:Antifungal Agents; D015220:Calcium Channels; D010972:Platelet Activating Factor; D017964:Itraconazole; D009240:N-Formylmethionine Leucyl-Phenylalanine; D002118:Calcium