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Mechanism for candidacidal activity in macrophages activated by recombinant gamma interferon

Candidacidal activity in macrophages activated by recombinant gamma interferon was examined kinetically in relation to acidification of phagolysosomes. In resident peritoneal macrophages (PMPs) of BALB/c mice, enhanced killing activity against Candida albicans was demonstrated after incubation with 100 U of gamma interferon per ml for 24 h but not after incubation for 48 to 72 h. Conversely, increased generation of H2O2 was exhibited in PMPs incubated from 48 to 72 h but not in PMPs incubated for 24 h. In normal PMPs, fusion of lysosomes to candida-containing phagosomes was readily accomplished and phagosome-lysosome fusion was not enhanced further by activation. The candidacidal substance was extracted from granule-rich fractions of either normal or activated PMPs by using citric acid (pH 2.7) in equal amounts; the substance showed a noncationic, heat-stable protein nature. In addition, when phagolysosomal pH was determined by flow cytometry of intraphagolysosomal fluorescein isothiocyanate-labeled C. albicans, phagolysosomes with low pH (less than 4.0) were detected in about 40% of PMPs activated for 24 h but not in those activated for 72 h or in normal PMPs. Moreover, increasing the intralysosomal pH with NH4Cl resulted in a significant reduction of candidacidal activity in activated PMPs. These results indicate that the candidacidal activity of gamma interferon-activated PMPs correlates well with enhanced acidification of their phagolysosomes and suggest that the candidacidal activity of activated PMPs is independent from reactive oxygen molecules and is mediated by proteinaceous substance(s) generated only in a strong acidic milieu of phagolysosomes by activation.