PREVENTION OF CORTICOSTEROID-INDUCED SUPPRESSION OF HUMAN POLYMORPHONUCLEAR LEUKOCYTE-INDUCED DAMAGE OF ASPERGILLUS-FUMIGATUS HYPHAE BY GRANULOCYTE-COLONY-STIMULATING FACTOR AND GAMMA-INTERFERON

Neutrophils (PMNs) are a critical line of defense against Aspergillus fumigatus infection. Increased frequency of invasive aspergillosis has been observed in patients receiving corticosteroids, suggesting a del eterious effect of these compounds on PMN antifungal function. To inve stigate this hypothesis and to determine the potential preventive util ity of granulocyte colony-stimulating factor (G-CSF) and gamma interfe ron (IFN-gamma), the effects of hydrocortisone (HCS) and dexamethasone (DXS) on PMN-induced damage of Aspergillus fumigatus hyphae were stud ied with or without pretreatment of PMNs with G-CSF and IFN-gamma. PMN s treated with HCS (greater-than-or-equal-to 3,000 muM) or DXS (greate r-than-or-equal-to 10 muM) during a 2-h colorimetric tetrazolium metab olic assay (using methylthiotetrazolium) showed suppressed percentage of hyphal damage (P < 0.02). In addition, both HCS (greater-than-or-eq ual-to 30 muM) and DXS (greater-than-or-equal-to 1 muM) significantly suppressed oxidative burst measured as superoxide anion release by PMN s in response to opsonized and nonopsonized hyphae as well as to N-for mylmethionyl leucyl phenylalanine. Pretreatment of PMNs with G-CSF (4, 000 U/ml) and/or IFN-gamma (100 and 1,000 U/ml) for 90 min prevented t he suppression of hyphal damage that occurred in the presence of HCS ( 3,000 muM; P < 0.01) or DXS (10 muM; P less-than-or-equal-to 0.001). G -CSF (4,000 U/ml) and IFN-gamma (100 U/ml) combined had an additive ef fect on increasing the antifungal activity of HCS-treated but not of D XS-treated PMNs compared with IFN-gamma alone (P = 0.015). Thus, these findings reveal that corticosteroids impair PMN function in response to A. fumigatus and that G-CSF and IFN-gamma prevent this impairment.