Interleukin (IL)-10 appears to play an important regulatory role in the systemic inflammatory response; however, production of IL-10 within the human central nervous system has not been described. Using cultures of human fetal microglial cells, the resident macrophages of the brain, we investigated the production and regulation of bioactive IL-10. Lipopolysaccharide stimulated acute release of tumor necrosis factor (TNF)-α (peak by 8 h) and delayed production of IL-10 (over a 48-h period) in microglial cell cultures. Treatment of microglial cell cultures with TNF-α and IL-6 resulted in a dose-dependent release of IL-10. These cytokines also induced expression of IL-10 mRNA. Treatment of microglial cell cultures with IL-10 markedly inhibited TNF-α and IL-6 production. These findings suggest that during inflammation within the brain, acute release of TNF-α and IL-6 by activated microglia could promote subsequent release of IL-10, which functions to minimize the potential neurotoxic effects of proinflammatory cytokines.