Production of Proinflammatory Cytokines and Chemokines During Neuroinflammation: Novel Roles for Estrogen Receptors α and β

Neuroinflammation is a common feature of many neurological disorders, and it is often accompanied by the release of proinflammatory cytokines and chemokines. Estradiol-17 beta (E(2)) exhibits antiinflammatory properties, including the suppression of proinflammatory cytokines, in the central nervous system. However, the mechanisms employed by E(2) and the role(s) of estrogen receptors (ERs) ER alpha and ER beta 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 + E(2)) mice. Brain levels of proinflammatory cytokines (IL-1 beta, IL-6, and IL-12p40) and chemokines (CCL2/MCP-1, CCL3/MIP-1 alpha, CCL5/RANTES, and CXCL1/KC) were quantified in mice at 0 (sham), 3, 6, 12, and 24 h after infection using multiplex protein analysis. E(2) treatment inhibited LPS-induced increases in all cytokines. In contrast, E(2) treatment only suppressed CCL/RANTES chemokine concentrations. To determine whether ER alpha and ER beta regulate brain cytokine and chemokine levels, parallel experiments were conducted using ER alpha knockout and ER beta knockout mice. Our results revealed that both ER alpha and ER beta regulated proinflammatory cytokine and chemokine production through E(2)-dependent and E(2)-independent mechanisms. To assess whether breakdown of the blood-brain barrier is an additional target of E(2) against LPS-induced neuroinflammation, we measured Evan's blue extravasation and identified distinct roles for ER alpha and ER beta. Taken together, these studies identify a dramatic cytokine- and chemokine-mediated neuroinflammatory response that is regulated through ER alpha- and ER beta-mediated ligand-dependent and ligand-independent mechanisms. (Endocrinology 151: 4916-4925, 2010)