Modulation of human microglial cell superoxide production by cytokines

Reactive oxygen intermediates (e,g., superoxide [O₂^-]) generated by microglia may play a role in host defense and injury within the central nervous system. We investigated the effect of cytokines on human microglial cell O₂^- production on stimulation with phorbol myristate acetate. Priming of microglial cell cultures with interferon-γ or tumor necrosis factor-a resulted in a dose- and time-dependent enhancement of O₂^- production. The priming effects of these cytokines were mediated through a protein kinase C signal transduction pathway. In contrast, astrocytes did not generate detectable O₂^- on phorbol myristate acetate stimulation. Treatment of microglia with transforming growth factor-β, interleukin-4, or interleukin -10 suppressed in a dose-dependent manner the priming effects of tumor necrosis factor-α and interferon-γ. The results of this study have implications for understanding the mechanisms by which cytokines and microglia contribute to processes of host defense and neurodegeneration via generation of reactive oxygen intermediates.