Selective modulation of BV-2 microglial activation by prostaglandin E-2 - Differential effects on endotoxin-stimulated cytokine induction

The influence of prostaglandins on glial functions and, more specifically, on glial activation is not well understood. We report here that prostagland in E-2 (PGE(2)), one of the major prostaglandins produced in the brain, act s as a potent and selective inhibitor of tumor necrosis factor alpha (TNF-a lpha) production in lipopolysaccharide-stimulated primary microglia and the microglial cell line BV-2. The IC50 for this effect is I nM, and 100 nM PG E(2) suppresses TNF-alpha production by >95%. More detailed studies of BV-2 cells show that PGE(2) also prevents the secretion of interleukin (IL)-6 b ut does not significantly modify lipopolysaccharide-stimulated expression o f cyclooxygenase-2, pro-IL-1 beta, or inducible nitric oxide synthase. PGE, appears to act primarily at the level of translation or protein stability, because TNF-alpha and IL-6 mRNA levels were only modestly decreased at hig h PGE(2) concentrations; concomitantly with this inhibition, PGE(2) up-regu lated the levels of IL-1 beta mRNA The effects of PGE(2) could be largely m imicked by 8-bromo-cAMP, suggesting that, as in other cell types, PGE(2) ac tion is mediated at least in part by a rise in intracellular cyclic AMP. Ho wever, the protein kinase A inhibitor H89 only partially reversed the inhib ition of TNF-alpha production by PGE(2), implying that the PGE(2) effect in BV-2 cells is mediated through both protein kinase A-dependent and A-depen dent pathways.