GPR30/GPER-1 mediates rapid decreases in TLR4 expression on murine macrophages.
Studies to define the effects of estrogens on immune function have yielded conflicting results. The recent demonstration that GPR30 can mediate rapid non-genomic events and may function as a novel transmembrane estrogen receptor could provide a mechanism underlying such findings. In this study, we have investigated the ability of GPR30 to regulate cell-surface expression of Toll-like receptor 4 (TLR4), a key molecule in the perception of bacterial lipopolysaccharide (LPS) by immune cells. We show that 17beta-estradiol or GPR30-specific agonists decrease TLR4 expression on macrophages within 10-60 min and such effects were abolished following GPR30 knockdown. Importantly, GPR30 ligation significantly reduces sensitivity of these immune cells to LPS challenge as determined by reductions in inflammatory mediator production. Based on these findings, we suggest that estrogen may utilize this non-classical estrogen receptor to limit potentially lethal acute inflammatory responses without compromising long-term host defense.
Rettew
Jennifer A
JA
Department of Biology, 9201 University City Boulevard, University of North Carolina at Charlotte, Charlotte, NC 28223, United States.
McCall
Samuel H
SH
Marriott
Ian
I
D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D055785:Gene Knockdown Techniques; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D034741:RNA, Small Interfering / Q000494:pharmacology; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D000954:Antigens, Surface; D004967:Estrogens; C532507:GPER1 protein, mouse; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4