Estrogen prevents the lipopolysaccharide-induced inflammatory response in microglia

After neuronal injury and in several neurodegenerative diseases, activated microglia secrete proinflammatory molecules that can contribute to the prog ressive neural damage. The recent demonstration of a protective role of est rogen in neurodegenerative disorders in humans and experimental animal mode ls led us to investigate whether this hormone regulates the inflammatory re sponse in the CNS. We here show that estrogen exerts an anti-inflammatory a ctivity on primary cultures of rat microglia, as suggested by the blockage of the phenotypic conversion associated with activation and by the preventi on of lipopolysaccharide-induced production of inflammatory mediators: indu cible form of NO synthase (iNOS), prostaglandin-E-2 (PGE(2)), and metallopr oteinase-9 (MMP-9). These effects are dose-dependent, maximal at 1 nM 17 be ta -estradiol, and can be blocked by the estrogen receptor (ER) antagonist ICI 182,780. The demonstration of ER alpha and ER beta expression in microg lia and macrophages and the observation of estrogen blockade of MMP-9 mRNA accumulation and MMP-9 promoter induction further support the hypothesis of a genomic activity of estrogen via intracellular receptors. This is the fi rst report showing an anti-inflammatory activity of estrogen in microglia. Our study proposes a novel explanation for the protective effects of estrog en in neurodegenerative and inflammatory diseases and provides new molecula r and cellular targets for the screening of ER ligands acting in the CNS.