Chorionic gonadotrophin regulates CXCR4 expression in human endometrium via E-series prostanoid receptor 2 signalling to PI3K-ERK1/2: implications for fetal-maternal crosstalk for embryo implantation.
Murine knock-out models and blastocyst co-culture studies have identified prostaglandin-endoperoxide synthase (PTGS) 2, prostaglandin (PG) E receptor 2 (PTGER2) and the chemokine receptor CXCR4 as important regulators of early pregnancy events. In vitro studies and studies in non-human primates have shown that these proteins are regulated in the endometrium by the early embryonic signal, chorionic gonadotrophin (CG). Here we show that expressions of PTGER2 and CXCR4 are elevated during the mid-secretory phase of the menstrual cycle and decidua of early pregnancy in humans. Using first trimester decidua explants, we show that CG induces expression of PTGS2 and biosynthesis of PGE₂, and expression of PTGER2. Subsequently, PGE₂via PTGER2 induces expression of CXCR4. Using an in vitro model system of Ishikawa endometrial epithelial cells stably expressing PTGER2 and human first trimester decidua explants, we demonstrate that CXCR4 expression is regulated by PTGER2 via the epidermal growth factor receptor (EGFR)-phosphatidylinositol-3-kinase (PI3K)-extracellular signal-regulated kinase (ERK1/2) pathway.Taken together, our data suggest that early embryonic signals may regulate fetal-maternal crosstalk in the human endometrium by inducing CXCR4 expression via the PGE₂-PTGER2-mediated induction of the EGFR, PI3K and ERK1/2 pathways.
Sales
Kurt J
KJ
Medical Research Council Human Reproductive Sciences Unit, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
Grant
Vivien
V
Catalano
Rob D
RD
Jabbour
Henry N
HN
D015153:Blotting, Western; D002460:Cell Line; D006063:Chorionic Gonadotropin / Q000494:pharmacology*; D003656:Decidua / Q000187:drug effects / Q000378:metabolism; D010064:Embryo Implantation / Q000235:genetics / Q000502:physiology*; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008597:Menstrual Cycle / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011247:Pregnancy; D011261:Pregnancy Trimester, First / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism*; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
C527276:CXCR4 protein, human; D006063:Chorionic Gonadotropin; C545644:PTGER2 protein, human; D019718:Receptors, CXCR4; D058307:Receptors, Prostaglandin E, EP2 Subtype; D019869:Phosphatidylinositol 3-Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3