title: Estrogen receptor alpha modulates mesangial cell responses to toll-like receptor ligands.
abstract: The female predominance in lupus is incompletely understood. The mechanisms for this difference are multifactorial involving the sex chromosomes, the hormones, and their receptors. We, and others, demonstrated that estrogen receptor alpha (ERα)-deficient female mice developed significantly less lupus-like renal disease. This protective effect of ERα deficiency occurred despite no impact on glomerular immune complex deposition. We hypothesized that decreased renal disease in ERα-deficient mice was due to a dampened renal response to inflammatory stimuli. Given the role of Toll-like receptors (TLRs) in lupus, we assessed whether there was an interaction between TLR responses and ERα. Herein, we show that TLR3, 4, and 7 ligands all enhanced mesangial cell (MC) ERα expression, whereas neither estrogen, nor ERα, impacted TLR3, 4, or 7 expression in MCs. The lack of ERα markedly decreased MC production of interleukin 6 and monocyte chemoattractant protein 1 (MCP-1) following addition of TLR3, 4, and 7 ligands. In MCs, TLR ligands induced ERα phosphorylation and nuclear localization. TLR3-induced nuclear factor κB nuclear translocation in MCs was not significantly affected by estrogen or ERα. Finally, we demonstrate that female MCs express more TLR3 and respond to TLR ligands with a significantly increased production of interleukin-6 compared with male MCs. These results identify a significant impact/interaction of ERα in TLR-mediated inflammatory responses in MCs.
authors.affiliation: Medical Research Service, Ralph H. Johnson VAMC and the Department of Medicine, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: John
authors.initials: J
authors.lastname: Svenson
authors.forename: Melissa
authors.initials: M
authors.lastname: Cunningham
authors.forename: Subhajit
authors.initials: S
authors.lastname: Dasgupta
authors.forename: Gary S
authors.initials: GS
authors.lastname: Gilkeson
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics*; D004967:Estrogens / Q000378:metabolism; D005260:Female; D015850:Interleukin-6 / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism; D008024:Ligands; D008181:Lupus Nephritis / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D050527:Mesangial Cells / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000378:metabolism
chemical_list: D000936:Antigen-Antibody Complex; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D047628:Estrogen Receptor alpha; D004967:Estrogens; D015850:Interleukin-6; D008024:Ligands; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse; C477038:Tlr7 protein, mouse; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7