Signaling through the membrane-bound estrogen receptor GPR30 induces IL10 and IL17A expression in Th17 cells (139.2)

Abstract

Abstract In 2005, the orphan G protein-coupled receptor GPR30 was shown to bind estrogen and mediate some downstream events associated with estrogen signaling. While work on GPR30-mediated suppression of autoimmune inflammation has been published, no definitive work on GPR30 in T cells has been reported. To address whether signaling through GPR30 can affect CD4+ T cell populations, CD4+CD62Lhi naïve T cells were stimulated in culture with anti-CD3/CD28 antibodies. We observed a dose-dependent increase in the number of IL10+ and IL10+IL17A+ cells in cultures treated with the GR30-directed agonist G-1, as measured by FACS. This effect is lost in cells from GPR30KO mice. Furthermore, the induction of IL10 and IL17A was limited to the RORγt+Foxp3- (Th17) population, while no effects were observed in Foxp3+ cells. Interestingly, the effects of systemic G-1 in the animal model T-cell mediated colitis varied between the peripheral compartment, where IL17A induction was again observed, and the GI mucosa, where a decrease in the number of IL17A+, IFNγ+, and TNFα+ cells was observed. These findings provide insight into the function of the membrane-bound estrogen receptor GPR30 in CD4+ T cell physiology. In addition, these data may help reconcile an apparent contradiction between work suggesting an immunosuppressive role for estrogen in several autoimmune disease models and clinical reality where women suffer from a substantially higher incidence of autoimmune disease.