GPER negatively regulates TNF&alpha;-induced IL-6 production in human breast cancer cells <i>via</i> NF-&kappa;B pathway

Abstract

Estrogen is known to have anti-inflammatory effects, that are thought to be mediated by the classical estrogen receptors (ERs), ERα and ERβ. 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 TNFα stimulation in the transfection of GPER-expression plasmid into HeLa cells. Exogenous GPER significantly inhibited TNFα-induced IL-6 expression, and blocked NF-κB 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 TNFα-induced IL-6 expression, probably through inhibition of NF-κB promoter activity by a signal(s) derived from the C-terminal region of GPER.

Expression and Role of the G Protein-Coupled Estrogen Receptor (GPR30/GPER) in the Development and Immune Response in Female Reproductive Cancers

“…It has been observed that GPER activation reduces TNFαinduced IL-6 expression in the SKBR3 cell line and reduces IL-6 and VEGF-A levels in triple-negative breast cancer cell lines MDA-MB-231 and BT-549 through inhibition of NF-κB transcriptional activity (83,107). Likewise, E2 prevented the action of TGF-β in the migration of MCF-7 and MDA-MB-231 breast cancer cell lines via GPER/ERK1/2, resulting in an inhibitory effect of Smad signaling (108).…”

Age and Gender-Related Changes in Renal Haemodynamics of Albino Rats: The Possible Role of Cytokines and Prostaglandins

“…GPER inhibits Tumor Necrosis Factor Alpha (TNF(x )-induced expression of Interleukin 6 (IL-6), one of the representative inflammatory cytokines. Furthermore, this inhibition was mediated via down-regulation of the nuclear factorkappa B (NF jB) promoter activity by GPER [72] .…”

The membrane‐type estrogen receptor G‐protein‐coupled estrogen receptor suppresses lipopolysaccharide‐induced interleukin 6 via inhibition of nuclear factor‐kappa B pathway in murine macrophage cells

“…1B). We recently reported that GPER negatively regulated TNFa-induced IL-6 expression in human breast cancer cells through repression of NF-jB transcriptional activity (Okamoto & Mizukami 2016). We examined whether treatment with G15, a selective GPER antagonist that has no effects on the classical nuclear ERs (Dennis et al 2009), reverses the G-1-related inhibition of LPS-induced IL-6 production; however, we could not observe the restoration of GPERmediated reduction of IL-6 production by the GPER antagonist, due to its toxicity on RAW264.7 cells (Fig.…”

“…In fact, in animal models of multiple sclerosis, deletion of the GPER gene led to the exacerbation of pathophysiological conditions induced by inflammatory processes; treatment with G-1, a selective GPER agonist that has no effects on the classical nuclear ERs (Bologa et al 2006), reduced the disease severity concomitant with a reduction in proinflammatory cytokines (Blasko et al 2009;Wang et al 2009;Yates et al 2010). Furthermore, this inhibition was mediated via down-regulation of the nuclear factor-kappa B (NF-jB) promoter activity by GPER (Okamoto & Mizukami 2016). Furthermore, aged male mice deficient in GPER showed a proinflammatory phenotype (Sharma et al 2013).…”

“…Although the molecular mechanisms of anti-inflammatory response by GPER remain unclear, we previously found that, in human breast cancer cells, GPER inhibits tumor necrosis factor alpha (TNFa)-induced expression of interleukin 6 (IL-6), one of the representative inflammatory cytokines. Furthermore, this inhibition was mediated via down-regulation of the nuclear factor-kappa B (NF-jB) promoter activity by GPER (Okamoto & Mizukami 2016). GPER is also expressed in macrophages that play an important role in innate immune response by producing inflammatory cytokines upon microbial invasion (Blasko et al 2009;Rettew et al 2010).…”