Decreased intracellular IL-33 impairs endometrial receptivity in women with adenomyosis

Adenomyosis is a common benign uterine lesion that is associated with female infertility, reduced clinical pregnancy rate and high miscarriage risk. While it has been known that the impaired endometrial receptivity is implicated in infertility in patients with adenomyosis, the underlying mechanism remains unclear. In the present study, we showed that intracellular protein level of IL-33 was downregulated in the endometrium of patients with adenomyosis, and IL-33 expression status was shown to be positively correlated with that of HOXA10, an endometrial receptivity marker. The subsequent analysis indicated IL-33 overexpression led to the increase of HOXA10 expression and enhancement of embryo implantation in vitro, which was accompanied with induction of STAT3 phosphorylation. Meanwhile, cryptotanshinone, a potent STAT3 inhibitor, was found to significantly suppress the increase of HOXA10 expression and embryo implantation caused by IL-33 overexpression in vitro, revealing the critical role of STAT3 activity. Consistently, the positive relationship between IL33 and HOXA10 expression in the endometrium was verified in the analysis of adenomyosis mouse model.