Production of proinflammatory cytokines and chemokines during neuroinflammation: Novel roles for estrogen receptors α and β

Candice M. Brown, Tara A. Mulcahey, Nicole C. Filipek, Phyllis M. Wise

Research output: Contribution to journalArticlepeer-review


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 mechanismsemployedby 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 E 2-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 ERαand ERβ regulate brain cytokine and chemokine levels, parallel experiments were conducted using ERαknockout and ERβknockout mice. Our results revealed that both ERαand ERβregulated 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 ERαand 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.

Original languageEnglish (US)
Pages (from-to)4916-4925
Number of pages10
Issue number10
StatePublished - Oct 2010
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology


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