Relaxin and prostaglandin E(2) regulate interleukin 11 during human endometrial stromal cell decidualization.

Decidualization of endometrial stromal cells and IL-11 signaling are essential for embryo implantation in the mouse. We investigated the effects of relaxin (RLX) and prostaglandin E(2) (PGE(2)) on IL-11 secretion by human endometrial stromal cells (HESC) and during cAMP or medroxyprogesterone acetate (P)-induced decidualization. cAMP-decidualized HESC secreted high levels of IL-11. RLX, cAMP, or PGE(2) increased IL-11 mRNA and IL-11 secretion, with maximal response to RLX and cAMP. Addition of the cAMP/protein kinase A inhibitor Rp-adenosine-3,5-cyclic-monophosphorothioate to either RLX- or PGE(2)-treated cells decreased IL-11 secretion. Indomethacin treatment decreased IL-11 secretion, which was largely restored by cotreatment with PGE(2) or RLX. Cotreatment of HESC with RLX, PGE(2), or cAMP and estrogen plus P down-regulated IL-11 mRNA and IL-11 secretion at 24 h, before secretion of prolactin (decidualization marker). Addition of W147AIL-11 (IL-11 signaling inhibitor) reduced prolactin secretion stimulated by RLX or PGE(2) and estrogen plus P. This is the first demonstration that cAMP-decidualized HESC secrete IL-11 and that IL-11 mRNA and IL-11 secretion are regulated by RLX and PGE(2), partly via a cAMP/protein kinase A-dependent pathway. Blocking IL-11 signaling reduced RLX+P- or PGE(2)+P-induced decidualization, suggesting that RLX and PGE(2) act via IL-11. This is important in understanding implantation and regulation of fertility.

IL-11 and IL-11Ralpha immunolocalisation at primate implantation sites supports a role for IL-11 in placentation and fetal development.

Embryo implantation, endometrial stromal cell decidualization and formation of a functional placenta are critical processes in the establishment and maintenance of pregnancy. Interleukin (IL)-11 signalling is essential for adequate decidualization in the mouse uterus and IL-11 promotes decidualization in the human. IL-11 action is mediated via binding to the specific IL-11 receptor alpha (IL-11Ralpha). The present study examined immunoreactive IL-11 and IL-11Ralpha in cycling rhesus monkey endometrium, at implantation sites in cynomolgus and rhesus monkeys and in human first trimester decidua and defined distinct spatial and temporal patterns. In cycling rhesus monkey endometrium, IL-11 and IL-11Ralpha increased in both basalis and functionalis regions during the secretory compared with the proliferative phase, with changing cellular locations in luminal and glandular epithelium and stroma. The patterns were similar overall to those previously described in human endometrium. Differences were seen in immunostaining during implantation in cynomologus and rhesus monkey. In the cynomolgus, very little staining for IL-11 or IL-11Ralpha was seen in syncytio- and cyto-trophoblast cells in the villi between days 12 and 150 of pregnancy although there was moderate staining in cytotrophoblast in the shell between days 12 and 17 and in subpopulations of cytotrophoblast cells invading the arteries at day 17. By contrast in the rhesus monkey between days 24 and 35 of pregnancy and in human first trimester placenta, cyto- and syncytio-trophoblast in the villi but not cytotrophoblast in the shell were positively stained. The most intense staining for both IL-11 and IL-11Ralpha was present within the decidua in the maternal component of implantation sites in all three primates but moderate staining was also present in maternal vascular smooth muscle and glands perivascular cells and epithelial plaques. These results are consistent with a role for IL-11 both during decidualization and placentation in primates.