| First Author | Brown CM | Year | 2010 |
| Journal | Endocrinology | Volume | 151 |
| Issue | 10 | Pages | 4916-25 |
| PubMed ID | 20685874 | Mgi Jnum | J:165675 |
| Mgi Id | MGI:4837992 | Doi | 10.1210/en.2010-0371 |
| Citation | Brown CM, et al. (2010) Production of proinflammatory cytokines and chemokines during neuroinflammation: novel roles for estrogen receptors alpha and beta. Endocrinology 151(10):4916-25 |
| abstractText | Neuroinflammation is a common feature of many neurological disorders, and it is often accompanied by the release of proinflammatory cytokines and chemokines. Estradiol-17beta (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) ERalpha and ERbeta 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-1beta, IL-6, and IL-12p40) and chemokines (CCL2/MCP-1, CCL3/MIP-1alpha, 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 ERalpha and ERbeta regulate brain cytokine and chemokine levels, parallel experiments were conducted using ERalpha knockout and ERbeta knockout mice. Our results revealed that both ERalpha and ERbeta 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 ERalpha and ERbeta. Taken together, these studies identify a dramatic cytokine- and chemokine-mediated neuroinflammatory response that is regulated through ERalpha- and ERbeta-mediated ligand-dependent and ligand-independent mechanisms. |
