Estrogen Receptor Alpha Modulates Mesangial Cell Responses to Toll-Like Receptor Ligands

摘要

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 (ER)-deficient female mice developed significantly less lupus-like renal disease. This protective effect of ER deficiency occurred despite no impact on glomerular immune complex deposition. We hypothesized that decreased renal disease in ER-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 ER. Herein, we show that TLR3, 4, and 7 ligands all enhanced mesangial cell (MC) ER expression, whereas neither estrogen, nor ER, impacted TLR3, 4, or 7 expression in MCs. The lack of ER 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 ER phosphorylation and nuclear localization. TLR3-induced nuclear factor B nuclear translocation in MCs was not significantly affected by estrogen or ER. 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 ER in TLR-mediated inflammatory responses in MCs.