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*ESTRADIOL
Endocrinology Vol. 141, No. 10 3646-3656
Copyright © 2000 by The Endocrine Society

ARTICLES

Antiinflammatory Effects of Estrogen on Microglial Activation1

Annadora J. Bruce-Keller, Jonathan L. Keeling, Jeffrey N. Keller, Feng F. Huang, Simonetta Camondola and Mark P. Mattson

Department of Anatomy and Neurobiology (A.J.B.-K., J.L.K.) and Sanders-Brown Center on Aging (J.N.K., F.F.H.), University of Kentucky, Lexington, Kentucky 40536; and Laboratory of Neurosciences, National Institute on Aging (S.C., M.P.M.), Baltimore, Maryland 21224

Address all correspondence and requests for reprints to: Dr. Annadora J. Bruce-Keller, Mn 210 Chandler Medical Center, University of Kentucky, Lexington, Kentucky 40536-0298. E-mail: abruce{at}pop.uky.edu

In the present study the effects of 17ß-estradiol on microglial activation are described. Estrogen replacement therapy has been associated with decreased severity of age-related neurodegenerative diseases such as Alzheimer’s disease, and estrogens have potent immunosuppressive properties outside of the brain. To determine the role that microglial cells might play in estrogen-mediated neuroprotection, primary rat microglia and N9 microglial cell lines were treated with increasing doses of 17ß-estradiol before or during immunostimulation by lipopolysaccharide, phorbol ester, or interferon-{gamma}. Pretreatment with 17ß-estradiol, but not 17{alpha}-estradiol or progesterone, dose dependently attenuated microglial superoxide release and phagocytic activity. Additionally, 17ß-estradiol attenuated increases in inducible nitric oxide synthase protein expression, but did not alter nuclear factor-{kappa}B activation. The antiinflammatory effects of 17ß-estradiol were blocked by the antiestrogen ICI 182,780. Additionally, 17ß-estradiol induced rapid phosphorylation of the p42/p44 mitogen-activated protein kinase (MAP kinase), and the MAP kinase inhibitor PD 98059 blocked the antiinflammatory effects of 17ß-estradiol. Overall, these results suggest that estrogen receptor-dependent activation of MAP kinase is involved in estrogen-mediated antiinflammatory pathways in microglial cells. These results describe a novel mechanism by which estrogen may attenuate the progression of neurodegenerative disease and suggest new pathways for therapeutic intervention in clinical settings.




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