Tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta produced by glial cells have been proposed bo play a role in various neurodenegerative diseases. The interaction of these two cytokines, however, is unknown. We tested the hypothesis that the TNF-alpha released from lipopolysaccharide (LPS)-treated murine microglial cells would stimulate the release of TGF-beta, which in turn would control TNF-alpha production. Treatment of murine microglial cell cultures with LPS resulted in an acute release of TNF-alpha (peak by 8 hr) followed by delayed release of bioactive TGF-beta (peak by 48 hr). Anti-TNF-alpha antibody significantly inhibited LPS-stimulated TGF-beta production, suggesting the involvement of TNF-alpha in TGF-beta production. Also, exogenous TNF-alpha induced in a dose-dependent fashion microglial cell expression of TGF-beta 1 mRNA and release of TGF-beta. Exogenous TGF-beta, on the other hand, suppressed LPS-stimulated TNF-alpha release. These findings suggest an autoregulation of microglial cell TNF-alpha production by TGF-beta which may limit inflammation-associated brain injury.