Antiinflammatory effects of estrogen on microglial activation

In the present study the effects of 17 beta-estradiol on microglial activat ion are described. Estrogen replacement therapy has been associated with de creased severity of age-related neurodegenerative diseases such as Alzheime r's disease, and estrogens have potent immunosuppressive properties outside of the brain. To determine the role that microglial cells might play in es trogen-mediated neuroprotection, primary rat microglia and N9 microglial ce ll lines were treated with increasing doses of 17 beta-estradiol before or during immunostimulation by lipopolysaccharide, phorbol ester, or interfero n-gamma. Pretreatment with 17 beta-estradiol, but not 17 alpha-estradiol or progesterone, dose dependently attenuated microglial superoxide release an d phagocytic activity. Additionally, 17 beta-estradiol attenuated increases in inducible nitric oxide synthase protein expression, but did not alter n uclear factor-kappa B activation. The antiinflammatory effects of 17 beta-e stradiol were blocked by the antiestrogen ICI 182,780. Additionally, 17 bet a-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 17 beta-estradiol. Overall, these results s uggest that estrogen receptor-dependent activation of MAP kinase is involve d in estrogen-mediated antiinflammatory pathways in microglial cells. These results describe a novel mechanism by which estrogen may attenuate the pro gression of neurodegenerative disease and suggest new pathways for therapeu tic intervention in clinical settings.