Tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-β produced by glial cells have been proposed to play a role in various neurodegenerative diseases. The interaction of these two cytokines, however, is unknown. We tested the hypothesis that the TNF-α released from lipopolysaccharide (LPS)-treated murine microglial cells would stimulate the release of TGF-β, which in turn would control TNF-α production. Treatment of murine microglial cell cultures with LPS resulted in an acute release of TNF-α (peak by 8 hr) followed by delayed release of bioactive TGF-β (peak by 48 hr). Anti-TNF-α antibody significantly inhibited LPS-stimulated TGF-β production, suggesting the involvement of TNF-α in TGF-β production. Also, exogenous TNF-α induced in a dose-dependent fashion microglial cell expression of TGF-β1 mRNA and release of TGF-β. Exogenous TGF-β, on the other hand, suppressed LPS-stimulated TNF-α release. These findings suggest an autoregulation of microglial cell TNF-α production by TGF-β which may limit inflammation-associated brain injury.