Figure 3

Summary of conceptus/uterine interactions from Day 12 to 18 of pregnancy. Exposure of the endometrium to progesterone secretion induces down-regulation of progesterone receptor (PGR) in the endometrial surface (LE) and glandular epithelium (GE). Progesterone modulation of uterine function is maintained by the presence of PR in stromal cells. Down-regulation of PGR in LE opens the window of receptivity of conceptus attachment to the endometrial surface. Progesterone stimulation increases PTGS2 within the LE increasing release of PGF2α into the uterine vasculature inducing CL regression during the estrous cycle. On Day 11 to 12 of pregnancy, conceptus epiblast expression of FGF4 stimulates production of BMP4 by the trophectoderm (Tr) to trigger differentiation of the mesoderm (meso) which may lead to induction of pathways to trigger conceptus trophoblast elongation. Embryonic IL1B2 initiates cellular remodeling during elongation and activates NFKB in the LE through binding to a functional IL1 receptor (IL1RI) and its receptor accessory protein (IL1RAcP). Activation of NFKB induces endometrial genes involved with inducing a pro-inflammatory response. IL1B2 activity in the conceptus and uterus is regulated through the level of receptor antagonist (IL1Rant) expression. Conceptus aromatase expression enhances estrogen secretion, which binds to ESR in the LE and GE increasing endometrial PGE production and altering the movement of PGs into the uterine lumen, thereby preventing luteolysis and maintaining pregnancy. Estrogen induction of STAT2 stimulates endometrial changes needed for placental attachment and may also play a role in modulating NFKB pro-inflammatory responses. Following conceptus elongation, IL1B2 expression ceases but is immediately replaced by expression of IFNγ and IFNδ and increased release of IL-18 into the uterine lumen. The activity of IL-18 is regulated through the concentration of its binding protein (IL-18BP). Activation of IFN-induced genes and conceptus PGE production may help regulate the pro-inflammatory response and regulate lymphocyte differentiation and activation within the uterine stroma and epithelium.