Lipoxin A4 Is A Novel Estrogen Receptor Agonist

Lipoxins (LXs), are endogenously produced eicosanoids, which possess potent antiinflammatory and proresolution bioactivities. The role of LXs in the endometrium is unknown. Our initial observations showed LXA4 enhanced estrogen receptor (ER)-mediated transcriptional activation in Ishikawa endometrial epithelial cells. Furthermore, we demonstrated that LXA4 possesses robust estrogenic activity through its capacity to alter cellular proliferation as well as the expression of estrogen-regulated genes implicated in cancer development. Interestingly, LXA4 also demonstrated antiestrogenic potential in that it attenuated E2-mediated cellular proliferation, consistent with the effects of a partial ER agonist. Subsequent studies revealed that these actions of LXA4 were directly mediated by ERa and appear to closely mimic those of the potent estrogen, 17b-Estradiol (E2). Using competitive radioligand binding assays, we confirmed that this lipid binds ER. We additionally demonstrated this estrogenic activity of LXA4 in mouse uterus in vivo using a uterotrophic assay and the expression of E2- dependent genes as readouts. Taken together our results establish a dual capacity of LXA4 to modulate estrogenic activity in the endometrium. These findings highlight a previously unappreciated paradigm in LXA4-mediated activities and reveal novel immunoendocrine crosstalk mechanisms. Disclosure of interest: None declared.