DIFFERENTIAL MODULATION OF ASTROCYTE CYTOKINE GENE-EXPRESSION BY TGF-BETA

In this study, we demonstrate that TGF-beta inhibits TNF-alpha express ion, and induces/enhances IL-6 expression by primary rat astrocytes. T reatment of astrocytes with TGF-beta alone had no effect on TNF-alpha mRNA or protein expression; however, TGF-beta suppressed induction of TNF-alpha expression by three different stimuli (IFN-gamma/LPS, IFN-ga mma/IL-1 beta, TNF-alpha) at both the protein and mRNA level. The exte nt of TGF-beta-mediated inhibition was greatest when astrocytes were p retreated with TGF-beta for 6 to 24 h, then exposed to the inducing st imuli. Inhibition of TNF-alpha mRNA steady-state levels by TGF-beta wa s a result of inhibition of TNF-alpha gene transcription, rather than degradation of the TNF-alpha message. In contrast, TGF-beta alone indu ced expression of IL-6 by astrocytes and synergized with two other cyt okines, IL-1 beta and TNF-alpha, for enhanced IL-6 expression. TGF-bet a-induced/enhanced IL-6 expression was mediated by transcriptional act ivation of the IL-6 gene. These results indicate that TGF-beta is an i mportant regulator of cytokine production by astrocytes under inflamma tory conditions in the brain.