Lipoxin A₄Blocks Embryo Implantation By Controlling Estrogen Receptor α Activity

Objective:Embryo implantation involves a complex regulatory network of steroid hormones, inflammatory cytokines and immune cells. Lipoxin A4(LXA4), a biologically active eicosanoid with specific anti-inflammatory and pro-resolving properties, was recently found to be a novel modulator of estrogen receptor a (ERa). In the present study, we investigated the potential role of LXA4in implantation, focusing on its influence on estrogen signaling.Methods:LXA4(10μg/kg) was administered to mice on days1-3of pregnancy. The mice were sacrificed on day5and the uteri were collected for determination of implantation sites or expression analysis.Results:LXA4blocked embryo implantation in mice and significantly reduced the expression of inflammatory mediators associated with uterine receptivity and embryo implantation, including corticotropin-releasing factor (CRF), cyclooxygenase2(COX2)-derived prostaglandin12(PGI2) and prostaglandin E2(PGE2), leukemia inhibitory factor (LIF) and interleukin6(IL6), but this effect was independent of LXA4receptor (ALX). Subsequent investigation revealed enhanced ERa activity in the uteri of LXA4-treated mice during the perumplantation period. ERa and phosphorylated ERa were significantly increased following LXA4treatment. Finally, it demonstrated that the inhibitory effect of LXA4on embryo implantation was mediated through ERa. In the presence of the ERa antagonist ICI, LXA4failed to block embryo implantation. LXA4also failed to inhibit CRF expression.Conclusion:These results suggested that LXA4blocks embryo implantation by controlling ERa activity, and this effect appeared to be related with the suppression of inflammatory microenvironment necessary for implantation.