Lipoxin A₄ is a novel estrogen receptor modulator

Inflammation is intimately linked with naturally occurring remodeling events in the endometrium. Lipoxins comprise a group of short-lived, non-classic eicosanoids possessing potent anti-inflammatory and proresolution properties. In the present study, we investigated the role of lipoxin A₄ (LXA₄) in the endometrium and demonstrated that 15-LOX-2, an enzyme necessary for LX biosynthesis, is expressed in this tissue. Our results establish that LXA₄ possesses robust estrogenic activity through its capacity to alter ERE transcriptional activity, as well as expression of estrogen- regulated genes, alkaline phosphatase activity, and proliferation in human endometrial epithelial cells. Interestingly, LXA₄ also demonstrated antiestrogenic potential, significantly attenuating E2-induced activity. This estrogenic activity was directly mediated through estrogen receptors (ERs). Subsequent investigations determined that the actions of LXA₄ are exclusively mediated through ERα and closely mimic those of the potent estrogen 17β-estradiol (E2). In binding assays, LXA₄ competed with E2 for ER binding, with an IC₅₀ of 46 nM. Furthermore, LXA₄ exhibited estrogenic activity in vivo, increasing uterine wet weight and modulating E2-regulated gene expression. These findings reveal a previously unappreciated facet of LXA₄ bioactions, implicating this lipid mediator in novel immunoendocrine crosstalk mechanisms.