Lipoxin A4 blocks embryo implantation by controlling estrogen receptor α activity.

ABSTRACT

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 α (ERα). In this study, we investigated the potential role of LXA4 in implantation. We found that LXA4 blocked embryo implantation in mice and significantly reduced the expression of inflammatory mediators associated with uterine receptivity and embryo implantation, including corticotropin-releasing factor (CRF), cyclooxygenase 2-derived prostaglandin I2 and prostaglandin E2, leukemia inhibitory factor, and interleukin 6, but this effect was independent of LXA4 receptor. Subsequent investigation revealed enhanced ERα activity in the uteri of LXA4-treated mice during the peri-implantation period. ERα and phosphorylated ERα were significantly increased following LXA4 treatment. Finally, it was demonstrated that the inhibitory effect of LXA4 on embryo implantation was mediated through ERα. In the presence of the ERα antagonist ICI 182 780, LXA4 failed to block embryo implantation. LXA4 also failed to inhibit CRF expression. These results suggested that LXA4 blocks embryo implantation by controlling ERα activity, and this effect appeared to be related to the suppression of the inflammatory microenvironment necessary for implantation.