In this study, we demonstrate that TGF-β inhibits TNF-α expression, and induces/enhances IL-6 expression by primary rat astrocytes. Treatment of astrocytes with TGF-β alone had no effect on TNF-α mRNA or protein expression; however, TGF-β suppressed induction of TNF-α expression by three different stimuli (IFN-γ/LPS, IFN-γ/IL-1β, TNF-α) at both the protein and mRNA level. The extent of TGF-β-mediated inhibition was greatest when astrocytes were pretreated with TGF-β for 6 to 24 h, then exposed to the inducing stimuli. Inhibition of TNF-α mRNA steady-state levels by TGF- β was a result of inhibition of TNF-α gene transcription, rather than degradation of the TNF-α message. In contrast, TGF-β alone induced expression of IL-6 by astrocytes and synergized with two other cytokines, IL- 1β and TNF-α, for enhanced IL-6 expression. TGF-β-induced/enhanced IL-6 expression was mediated by transcriptional activation of the IL-6 gene. These results indicate that TGF-β is an important regulator of cytokine production by astrocytes under inflammatory conditions in the brain.