Estrogen anti-inflammatory activity on human monocytes is mediated through cross-talk between estrogen receptor ERα36 and GPR30/GPER1

Abstract

Estrogens are known modulators of monocyte/macrophage functions; however, the underlying mechanism has not been clearly defined. Recently, a number of estrogen receptor molecules and splice variants were identified that exert different and sometimes opposing actions. We assessed the expression of estrogen receptors and explored their role in mediating estrogenic anti-inflammatory effects on human primary monocytes. We report that the only estrogen receptors expressed are estrogen receptor-α 36-kDa splice variant and G-protein coupled receptor 30/G-protein estrogen receptor 1, in a sex-independent manner. 17-β-Estradiol inhibits the LPS-induced IL-6 inflammatory response, resulting in inhibition of NF-κB transcriptional activity. This is achieved via a direct physical interaction of ligand-activated estrogen receptor-α 36-kDa splice variant with the p65 component of NF-κB in the nucleus. G-protein coupled receptor 30/G-protein estrogen receptor 1, which also physically interacts with estrogen receptor-α 36-kDa splice variant, acts a coregulator in this process, because its inhibition blocks the effect of estrogens on IL-6 expression. However, its activation does not mimic the effect of estrogens, on neither IL-6 nor NF-κB activity. Finally, we show that the estrogen receptor profile observed in monocytes is not modified during their differentiation to macrophages or dendritic cells in vitro and is shared in vivo by macrophages present in atherosclerotic plaques. These results position estrogen receptor-α 36-kDa splice variant and G-protein coupled receptor 30 as important players and potential therapeutic targets in monocyte/macrophage-dependent inflammatory processes.

Impact of sarcopenia in borderline resectable and locally advanced pancreatic cancer patients receiving stereotactic body radiation therapy

“…Postmenopausal females may be particularly predisposed to sarcopenia due to the absence of the anabolic effects of circulating testosterone in addition to losing the anti-inflammatory effects of estrogen. Estrogen has been shown to have anti-inflammatory properties and men continue to aromatize estrogen so long as they have circulating testosterone (50)(51)(52)(53)(54)(55)(56)(57)(58)(59). In our study, we did not have data on whether our post-menopausal patients were on estrogen replacement therapy (ERT) and future studies are needed to compare the rate of sarcopenia and complications in this patient group.…”

G Protein-Coupled Receptor 30 (GPR30) Expression Pattern in Inflammatory Bowel Disease Patients Suggests its Key Role in the Inflammatory Process. A Preliminary Study

“…There are already several lines of evidence showing that GPR30 is expressed in macrophages, neutrophils and lymphocytes, e.g. Tregs [27][28][29][30][31][32].…”

“…It was shown that GPR30 is involved, among others, in the J Gastrointestin Liver Dis, March 2017 Vol. 26 No 1: [29][30][31][32][33][34][35] activation of actin polymerization and the inhibition of cellular proliferation in human umbilical vein endothelial cells [13]; others found that the GPR30 agonist inhibits cardiac cell growth [14]. Recent studies implicate the role of GPR30 in aggressive forms of breast, ovarian and endometrial cancers [15].…”

“…The idiopathic J Gastrointestin Liver Dis, March 2017 Vol. 26 No 1: [29][30][31][32][33][34][35] inflammatory intestinal process related to IBD is strongly associated with a decreased patient's quality of life and requires advanced clinical intervention. However, a significant rate of loss of response or even the lack of any therapeutic effect is often observed with currently available anti-IBD treatments.…”

Alpha-Lipoic Acid Protects Human Aortic Endothelial Cells Against H2O2-Induced Injury and Inhibits Atherosclerosis in Ovariectomized Low Density Lipoprotein Receptor Knock-Out Mice

“…Compared with premenopausal women, postmenopausal women have a higher incidence of cardiovascular disease due to loss of responsiveness to either internal or even externally provided estrogen [3]. It has been postulated that estrogen deficiency contributes to the high morbidity of atherosclerosis in postmenopausal women through a role in numerous atherogenic processes, including inflammation [4,5], vascular smooth muscle cell proliferation [6], generation of reactive oxygen species (ROS) [7], and apoptosis of vascular endothelial cells [8]. Some studies have demonstrated that hormone replacement therapy (HRT) can lower the risk of cardiovascular disease in postmenopausal women, but only when therapy is initiated in the early stages after menopause [9][10][11][12].…”