The mechanisms of glucocorticoid-induced immunosuppression of human monocytes for the defense of Candida albicans were examined in this in vitro study. Dexamethasone at pharmacological concentrations (10(-7)-10(-5) M) dose-dependently attenuated growth inhibition of C. albicans by resident monocytes. In interferon-gamma (IFN-gamma)-primed monocytes, fungal growth inhibition was maximal and not altered by dexamethasone. Similarly, phagocytosis and killing of Candida by monocytes were not affected by steroids. To study the underlying mechanisms, we found that Candida-induced synthesis of tumor necrosis factor-alpha (TNF-alpha) by monocytes was completely abrogated by dexamethasone. Substitution of TNF-alpha to dexamethasone-treated monocytes fully reversed the alterations of growth inhibition of C. albicans induced by steroids. These findings suggest that glucocorticoids affect the growth control of Candida by monocytes indirectly via suppression of the formation of TNF-alpha, which is required as an autocrine cofactor for full monocyte activation.