Because IL-1 is implicated in the pathogenesis of multiple sclerosis, and IFNs are known to alter disease course, we sought to determine whether IFNs can regulate the expression of IL-1 and IL-1R antagonist (IL-1Ra) in primary cultures of human microglia and astrocytes. We found that IL-1 and IL-1Ra are products of microglia but not astrocytes, and IFN-β and IFN-γ differentially modulate LPS-and cytokine-induced IL-1 and IL-1Ra. IFN-β induces IL-1Ra and augments LPS-and IL-4-induced IL-1Ra, but suppresses LPS-and IL-1-induced IL-1, shifting the balance toward the expression of the IL-1Ra. Like IFN-β, IFN-γ suppresses the expression of both LPS and IL-1-induced IL-1β. However, IFN-γ also suppresses the expression of IFN-β-and IL-4-induced IL-1Ra so that IFN-γ may enhance or suppress IL-1 activity depending on the other cytokines present. IL-4 has similar effects to IFN-β; however, other anti-inflammatory cytokines, did not regulate IL-1 or IL-1Ra in human microglia. Our data demonstrate a novel suppressive effect of IFN-β and IL-4 on IL-1 activity in human microglia, suggesting that IFN-β, a therapeutic agent used for multiple sclerosis, could have wider applications in the treatment of other central nervous system disorders in which IL-1 activity has been implicated in the pathogenesis.