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.