Selective modulation of BV-2 microglial activation by prostaglandin E₂. 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 prostaglandin E₂ (PGE₂), one of the major prostaglandins produced in the brain, acts as a potent and selective inhibitor of tumor necrosis factor α (TNF-α) production in lipopolysaccharide-stimulated primary microglia and the microglial cell line BV-2. The IC₅₀ for this effect is 1 nM, and 100 nM PGE₂ suppresses TNF-α production by >95%. More detailed studies of BV-2 cells show that PGE₂ also prevents the secretion of interleukin (IL)-6 but does not significantly modify lipopolysaccharide-stimulated expression of cyclooxygenase-2, pro-IL-1β, or inducible nitric oxide synthase. PGE₂ appears to act primarily at the level of translation or protein stability, because TNF-α and IL-6 mRNA levels were only modestly decreased at high PGE₂ concentrations; concomitantly with this inhibition, PGE₂ up-regulated the levels of IL-1β mRNA. The effects of PGE₂ could be largely mimicked by 8-bromo-cAMP, suggesting that, as in other cell types, PGE₂ action is mediated at least in part by a rise in intracellular cyclic AMP. However, the protein kinase A inhibitor H89 only partially reversed the inhibition of TNF- α production by PGE₂, implying that the PGE₂ effect in BV-2 cells is mediated through both protein kinase A-dependent and -independent pathways.