Chorionic Gonadotropin Regulates Prostaglandin E Synthase via a Phosphatidylinositol 3-Kinase-Extracellular Regulatory Kinase Pathway in a Human Endometrial Epithelial Cell Line: Implications for Endometrial Responses for Embryo Implantation

Abstract

Successful implantation necessitates modulation of the uterine environment by the embryo for a specific period of time during the menstrual cycle. Infusion of chorionic gonadotropin (CG) into the oviducts of baboons to mimic embryo transit induces a myriad of morphological, biochemical, and molecular changes in the endometrium. Endometrial epithelial cells from both baboons and humans when stimulated by CG in vitro, activates a cAMP-independent MAPK pathway leading to prostaglandin E(2) (PGE(2)) synthesis. This study shows that in the human endometrial cell line, HES, CG, acting via its G-protein coupled receptor, phosphorylates protein kinase B, c-Raf, and ERK1/2 in a phosphatidylinositol 3-kinase (PI3K)-dependent manner. Furthermore, ERK1/2 phosphorylation is independent of the signaling paradigms of Galpha(s), Galpha(I), and epidermal growth factor receptor (EGFR) transactivation, typical of gonadal cells, indicating an alternative signaling pattern in the endometrium. After phosphorylation by CG, ERK1/2 translocates to the nucleus in a time-dependent manner. Downstream of ERK1/2, CG activates the nuclear transcription factor, Elk1, also in a PI3K-MAPK-dependent manner. Lastly, we show that in HES cells, this pathway regulates the expression of the microsomal enzyme PGE(2) synthase (mPTGES), a terminal prostanoid synthase responsible for PGE(2) synthesis. CG regulates the mPTGES promoter and also induces mPTGES synthesis in HES cells via the PI3K-ERK1/2 pathway. We suggest that this alternative PI3K-ERK-Elk pathway activated by CG regulates prostaglandin production by the endometrial epithelium and serves as an early trigger to prepare the endometrium for implantation.

Novel insights into the mechanisms of pregnancy establishment: regulation of prostaglandin synthesis and signaling in the pig

“…Moreover, a recent study showed that the human embryonic signal, chorionic gonadotropin, regulates the mPGES-1 promoter and induces mPGES-1 synthesis in endometrial epithelial cells via the PI3K-ERK1/2 pathway (Banerjee et al 2009). Interestingly, in rats, mPGES-1 mRNA and protein were only detected in the subluminal stroma surrounding the implanting blastocyst at the implantation site on day 6 of pregnancy, but were not observed in the inter-implantation site on day 6 of pregnancy and on day 6 of pseudopregnancy (Cong et al 2006).…”

EMMPRIN Is Secreted by Human Uterine Epithelial Cells in Microvesicles and Stimulates Metalloproteinase Production by Human Uterine Fibroblast Cells

“…30,31 The HES cells were cultured, passaged, and maintained in phenol red-free, high glucose Dulbecco Modified Eagle Medium (Invitrogen, Carlsbad, California) supplemented with 10% FBS (Atlanta Biologicals) and 120 U/mL penicillin/streptomycin (Cambrex). Once cells reached confluency, they were transferred to serum-free medium containing only antibiotics for 24 hours and then conditioned medium (CM) was collected.…”

Implantation and Establishment of Pregnancy in Human and Nonhuman Primates

“…Prostaglandin E2 (PGE2) induces cAMP in endometrial stromal cells to promote their predecidualization response during the secretory phase (Tanaka et al 1993). According to results from our and other laboratories, treatment of both human and baboon endometrial epithelial cells with CG induces expression of cyclooxigenase-2 (COX2, coded by PTGS2 ) and prostaglandin E synthase (PGES), two enzymes that control the synthesis of PGE2 (Banerjee et al 2009; Zhou et al 1999), as well as the production of PGE2 (Srisuparp et al 2003). The response of endometrial epithelial cells to CG and the downstream PGE2 production occurs through the CG receptor LHCGR, a seven transmembrane G protein-coupled receptor, and the inositol phosphate-dependent mitogen-activated protein kinases (MAPK) pathway (Banerjee et al 2009).…”

“…According to results from our and other laboratories, treatment of both human and baboon endometrial epithelial cells with CG induces expression of cyclooxigenase-2 (COX2, coded by PTGS2 ) and prostaglandin E synthase (PGES), two enzymes that control the synthesis of PGE2 (Banerjee et al 2009; Zhou et al 1999), as well as the production of PGE2 (Srisuparp et al 2003). The response of endometrial epithelial cells to CG and the downstream PGE2 production occurs through the CG receptor LHCGR, a seven transmembrane G protein-coupled receptor, and the inositol phosphate-dependent mitogen-activated protein kinases (MAPK) pathway (Banerjee et al 2009). Interestingly, treatment with CG failed to induce production of cAMP in endometrial epithelial cells, but leads to a release of PGE2 which induces cAMP production in stromal cells (Srisuparp et al 2003; Tanaka et al 1993), suggesting the role of epithelial cells mediating the stromal response to embryonic CG.…”