GPER negatively regulates TNFa-induced IL-6 production in human breast cancer cells via NF-?B pathway.

Endocrine journal

PubMedID: 26888479

Okamoto M, Mizukami Y. GPER negatively regulates TNFa-induced IL-6 production in human breast cancer cells via NF-?B pathway. Endocr J. 2016;.
Estrogen is known to have anti-inflammatory effects, that are thought to be mediated by the classical estrogen receptors (ERs), ERa and ERß. G protein coupled estrogen receptor1 (GPER) is a novel membrane-type estrogen receptor that can mediate non-genomic estrogenic responses. Although there have been several reports asserting that the participation of GPER in anti-inflammatory effects is induced by estrogen, the role of GPER remains poorly understood. In this study, we investigated the involvement of GPER in the regulation of a representative inflammatory cytokine, IL-6. We first examined the expression of IL-6 mRNA by TNFa stimulation in the transfection of GPER-expression plasmid into HeLa cells. Exogenous GPER significantly inhibited TNFa-induced IL-6 expression, and blocked NF-?B promoter activity inducing the expression of IL-6 in a dose-dependent manner. The promoter activity was restored almost to control level by transfection with the C-terminal deletion mutant of GPER. Similar results have been observed in endogenous GPER using SKBR3 cells which do not express the classical ERs. The data have been validated by treatment of GPER with siRNA. These findings indicate that GPER negatively regulates TNFa-induced IL-6 expression, probably through inhibition of NF-?B promoter activity by a signal(s) derived from the C-terminal region of GPER.