title: Estrogen modulates microglial inflammatory mediator production via interactions with estrogen receptor beta.
abstract: Estrogens are well known to exert antiinflammatory effects outside the central nervous system (CNS). They have also been shown to exert neuroprotective effects in the CNS after several types of injury, including neurodegeneration. However, the molecular mechanisms by which these effects occur remain unclear. Because microglial hyperactivation and their production of neurotoxins is associated with many types of brain injury for which estrogens are beneficial, we sought to investigate the ability of estrogen to modulate microglial function. Furthermore, because little is known regarding the role of each of the two known estrogen receptors (ERs) in microglia, our studies were designed to test the hypothesis that 17beta-estradiol (E(2)) exerts antiinflammatory effects in microglia, specifically via interactions with ERbeta. We tested this hypothesis using the murine microglial cell line BV-2, which naturally expresses only ERbeta. Our results indicate that not only does E(2) decrease lipopolysaccharide (LPS)-stimulated nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression, it also reduces the expression of cyclooxygenase-2, a target for estrogen that has not previously been reported for ERbeta. We also observed that LPS-stimulated TNFalpha mRNA was increased by estrogen. E(2) exerts these effects within 30 min compared with typical estrogen transcriptional responses. Tamoxifen and ICI 182,780 differentially blocked the inhibitory effects of E(2) on LPS-stimulated iNOS and cyclooxygenase-2. In addition, we show that E(2) alters LPS-stimulated MAPK pathway activation, supporting the idea that alterations in the MAPKs may be a potential mechanism by which ERbeta mediates decreased microglial activation.
authors.affiliation: Department of Comparative Biosciences, 2015 Linden Drive, Madison, Wisconsin 53706, USA. jjwatters@wisc.edu
authors.forename: Ann E
authors.initials: AE
authors.lastname: Baker
authors.forename: Vielska M
authors.initials: VM
authors.lastname: Brautigam
authors.forename: Jyoti J
authors.initials: JJ
authors.lastname: Watters
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D004789:Enzyme Activation / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004964:Estriol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D000077267:Fulvestrant; D018836:Inflammation Mediators / Q000378:metabolism*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D018836:Inflammation Mediators; D007527:Isoenzymes; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D004964:Estriol