Endometrial response to conceptus-derived estrogen and interleukin-1β at the time of implantation in pigs

Abstract

The establishment of pregnancy is a complex process that requires a well-coordinated interaction between the implanting conceptus and the maternal uterus. In pigs, the conceptus undergoes dramatic morphological and functional changes at the time of implantation and introduces various factors, including estrogens and cytokines, interleukin-1β2 (IL1B2), interferon-γ (IFNG), and IFN-δ (IFND), into the uterine lumen. In response to ovarian steroid hormones and conceptus-derived factors, the uterine endometrium becomes receptive to the implanting conceptus by changing its expression of cell adhesion molecules, secretory activity, and immune response. Conceptus-derived estrogens act as a signal for maternal recognition of pregnancy by changing the direction of prostaglandin (PG) F_2α from the uterine vasculature to the uterine lumen. Estrogens also induce the expression of many endometrial genes, including genes related to growth factors, the synthesis and transport of PGs, and immunity. IL1B2, a pro-inflammatory cytokine, is produced by the elongating conceptus. The direct effect of IL1B2 on endometrial function is not fully understood. IL1B activates the expression of endometrial genes, including the genes involved in IL1B signaling and PG synthesis and transport. In addition, estrogen or IL1B stimulates endometrial expression of IFN signaling molecules, suggesting that estrogen and IL1B act cooperatively in priming the endometrial function of conceptus-produced IFNG and IFND that, in turn, modulate endometrial immune response during early pregnancy. This review addresses information about maternal-conceptus interactions with respect to endometrial gene expression in response to conceptus-derived factors, focusing on the roles of estrogen and IL1B during early pregnancy in pigs.

Keywords: Conceptus; Endometrium; Estrogen; Interleukin-1β, Pig; Uterus.

Fig. 1

Profiles of major hormones in the blood during the estrous cycle (a) and pregnancy (b) in pigs. a. During the estrous cycle estrogen concentrations increase prior to estrus by the coordinated actions of gonadotropin-releasing hormone (GnRH), follicle stimulating hormone (FSH), and luteinizing hormone (LH) and decrease on the day of estrus. Progesterone concentrations increase rapidly on the day of estrus until d 12–d 14 and decrease rapidly from d 15 of the estrous cycle due to regression of the corpus luteum induced by prostaglandin (PG) F_2α (PGF) from the endometrium. b. During pregnancy estrogen concentrations decrease from estrus, maintain low concentrations with brief increases on around d 12 and d 25–d 30 of pregnancy, and increase prior to parturition. Progesterone concentrations increase from estrus to reach maximum concentrations on d 12–d 14, then decrease slowly until d 30, and remain fairly constant throughout pregnancy until near term. Developmental processes that occur in the female reproductive tract and morphological changes of preimplantation embryos and early stage conceptuses to corresponding days of pregnancy are indicated on top. Elongating conceptuses on around d 12 of pregnancy secrete estrogen and interleukin-1β2 (IL1B2), and the implanting conceptuses produce maximum levels of interferon-δ (IFND) and IFN-γ (IFNG) on around d 14–d 16. The endometrium and conceptus produce PGs on d 12, and the endometrium produces PGF to induce parturition at term

Fig. 2

Working model of the role of lysophosphatidic acid (LPA) at the maternal-conceptus interface in pigs. Estrogen of conceptus origin induces endometrial epithelial expression of LPA receptor 3 (LPAR3), and ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) activates endometrial production of LPA. LPAs secreted into the uterine lumen act on endometrial luminal (LE) and glandular epithelial (GE) cells to increase the expression of prostaglandin (PG)-endoperoxide synthase 2 (PTGS2), which in turn acts on the production of PGF_2α and PGE₂. LPAs also act on the conceptus trophectoderm to activate the extracellular signal-regulated kinases 1/2 (ERK1/2) and p90 ribosomal S6 kinase (P90RSK) signaling pathway and the p38 mitogen-activated protein kinase (MAPK) signaling pathway, which induces the expression of urokinase-type plasminogen activator (PLAU) and PTGS2

Fig. 3

Schematic illustration of the effects of conceptus-derived factors on the expression of genes and possible functions in the endometrium of the porcine uterus during early pregnancy in pigs. Estrogens (E2) and interleukin-1β (IL1B) are secreted by the elongated filamentous conceptus into the uterine lumen on d 11-12 of pregnancy and affect the expression of many endometrial genes, including Aldo-keto reductase 1B1 (AKR1B1), ATP-binding cassette sub-family C member 4 (ABCC4), prostaglandin (PG)-endoperoxide synthases 1 and 2 (PTGS1, PTGS2), and solute carrier organic anion transporter family, member 2A1 (SLCO2A1), that are involved in PG synthesis and transport, leading to the maternal recognition of pregnancy. In addition, E2 and IL1B induce endometrial expression of several interferon (IFN) signaling molecules, including receptors for type I and type II IFNs and IFN-regulatory factor 1 (IRF1) and signal transducers and signal transduction and activator of transcription 1 (STAT1), to prime the endometrium to increase its responsiveness to the actions of IFN-γ (IFNG) and IFN-δ (IFND), which are secreted by the conceptus following its production of estrogen and IL1B on d 12-20 of pregnancy. IFNG and IFND change the endometrial immune environment, increasing maternal immunity for protection and achieving maternal immune tolerance to the semi-allograft conceptus