| Production of proinflammatory cytokines and chemokines during neuroinflammation: novel roles for estrogen receptors alpha and beta. | |
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MedLine Citation:
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PMID: 20685874 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Neuroinflammation is a common feature of many neurological disorders, and it is often accompanied by the release of proinflammatory cytokines and chemokines. Estradiol-17β (E2) exhibits antiinflammatory properties, including the suppression of proinflammatory cytokines, in the central nervous system. However, the mechanisms employed by E2 and the role(s) of estrogen receptors (ERs) ERα and ERβ are unclear. To investigate these mechanisms, we employed an in vivo lipopolysaccharide (LPS) model of systemic inflammation in ovariectomized (OVX) and OVX and E2-treated (OVX+E2) mice. Brain levels of proinflammatory cytokines (IL-1β, IL-6, and IL-12p40) and chemokines (CCL2/MCP-1, CCL3/MIP-1α, CCL5/RANTES, and CXCL1/KC) were quantified in mice at 0 (sham), 3, 6, 12, and 24 h after infection using multiplex protein analysis. E2 treatment inhibited LPS-induced increases in all cytokines. In contrast, E2 treatment only suppressed CCL/RANTES chemokine concentrations. To determine whether ERα and ERβ regulate brain cytokine and chemokine levels, parallel experiments were conducted using ERα knockout and ERβ knockout mice. Our results revealed that both ERα and ERβ regulated proinflammatory cytokine and chemokine production through E2-dependent and E2-independent mechanisms. To assess whether breakdown of the blood-brain barrier is an additional target of E2 against LPS-induced neuroinflammation, we measured Evan's blue extravasation and identified distinct roles for ERα and ERβ. Taken together, these studies identify a dramatic cytokine- and chemokine-mediated neuroinflammatory response that is regulated through ERα- and ERβ-mediated ligand-dependent and ligand-independent mechanisms. |
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Authors:
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Candice M Brown; Tara A Mulcahey; Nicole C Filipek; Phyllis M Wise |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-08-04 |
Journal Detail:
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Title: Endocrinology Volume: 151 ISSN: 1945-7170 ISO Abbreviation: Endocrinology Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-09-22 Completed Date: 2010-11-04 Revised Date: 2012-05-07 |
Medline Journal Info:
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Nlm Unique ID: 0375040 Medline TA: Endocrinology Country: United States |
Other Details:
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Languages: eng Pagination: 4916-25 Citation Subset: AIM; IM |
Affiliation:
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Department of Physiology and Biophysics, University of Washington, Box 356460, Seattle, Washington 98195-4640, USA. canbrown@uw.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Blood-Brain Barrier / drug effects, metabolism Brain / drug effects, immunology, metabolism, pathology Cell Membrane Permeability / drug effects, genetics Chemokines / biosynthesis* Cytokines / biosynthesis* Estradiol / pharmacology Estrogen Receptor alpha / genetics, metabolism, physiology* Estrogen Receptor beta / genetics, metabolism, physiology* Female Inflammation Mediators / metabolism* Lipopolysaccharides / pharmacology Mice Mice, Inbred C57BL Mice, Knockout Neuritis / chemically induced, genetics*, immunology, metabolism* Neuroimmunomodulation / drug effects, genetics |
| Grant Support | |
ID/Acronym/Agency:
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AG002224/AG/NIA NIH HHS; F32AG027614/AG/NIA NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Chemokines; 0/Cytokines; 0/Estrogen Receptor alpha; 0/Estrogen Receptor beta; 0/Inflammation Mediators; 0/Lipopolysaccharides; 50-28-2/Estradiol |
| Comments/Corrections | |
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