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Estrogen Modulates Microglial Inflammatory Mediator Production via Interactions with Estrogen Receptor ß

Department of Comparative Biosciences (A.E.B., V.M.B., J.J.W.) and Program in Endocrinology and Reproductive Physiology (A.E.B., J.J.W.), University of Wisconsin, Madison, Wisconsin 53706

Address all correspondence and requests for reprints to: Jyoti J. Watters, Ph.D., Department of Comparative Biosciences, 2015 Linden Drive, Madison, Wisconsin 53706. E-mail: jjwatters{at}wisc.edu.

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 17ß-estradiol (E₂) exerts antiinflammatory effects in microglia, specifically via interactions with ERß. We tested this hypothesis using the murine microglial cell line BV-2, which naturally expresses only ERß. Our results indicate that not only does E₂ 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 ERß. We also observed that LPS-stimulated TNF mRNA was increased by estrogen. E₂ exerts these effects within 30 min compared with typical estrogen transcriptional responses. Tamoxifen and ICI 182,780 differentially blocked the inhibitory effects of E₂ on LPS-stimulated iNOS and cyclooxygenase-2. In addition, we show that E₂ alters LPS-stimulated MAPK pathway activation, supporting the idea that alterations in the MAPKs may be a potential mechanism by which ERß mediates decreased microglial activation.

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