Inhibition of microglial cell RANTES production by IL-10 and TGF-beta

Using human fetal microglial cell cultures, we found that the gram-negative bacterial cell wall component lipopolysaccharide (LPS) stimulated RANTES ( regulated upon activation of normal T cell expressed and secreted) producti on through the protein kinase C signaling pathway and that activation of tr anscription nuclear factor (NF)-kappa B was required for this effect. Simil arly, the proinflammatory cytokines interleukin (IL)-1 beta and tumor necro sis factor-alpha dose-dependently stimulated microglial cell RANTES product ion via NF-kappa B activation. Anti-inflammatory cytokines, IL-10, and tran sforming growth factor (TGF)-beta sequentially inhibited LPS- and cytokine- induced microglial cell NF-kappa B activation, RANTES mRNA expression, and protein release. Proinflammatory cytokines but not LPS also stimulated RANT ES production by human astrocytes. These findings demonstrate that human mi croglia synthesize RANTES in response to proinflammatory stimuli, and that the anti-inflammatory cytokines IL-10 and TGF-beta down-regulate the produc tion of this beta-chemokine. These results may have important therapeutic i mplications for inflammatory diseases of the brain.