Antiinflammatory effects of estrogen on microglial activation.
In the present study the effects of 17beta-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 17beta-estradiol before or during immunostimulation by lipopolysaccharide, phorbol ester, or interferon-gamma. Pretreatment with 17beta-estradiol, but not 17alpha-estradiol or progesterone, dose dependently attenuated microglial superoxide release and phagocytic activity. Additionally, 17beta-estradiol attenuated increases in inducible nitric oxide synthase protein expression, but did not alter nuclear factor-KB activation. The antiinflammatory effects of 17beta-estradiol were blocked by the antiestrogen ICI 182,780. Additionally, 17beta-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 17beta-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.
Bruce-Keller
A J
AJ
Department of Anatomy and Neurobiology, University of Kentucky, Lexington 40536, USA. abruce@pop.uky.edu
Keeling
J L
JL
Keller
J N
JN
Huang
F F
FF
Camondola
S
S
Mattson
M P
MP
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D000077267:Fulvestrant; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010587:Phagocytosis / Q000187:drug effects; D051381:Rats; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D005419:Flavonoids; D016328:NF-kappa B; D011960:Receptors, Estrogen; D013481:Superoxides; D000077267:Fulvestrant; D004958:Estradiol; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one