Ka et al. Journal of Animal Science and Biotechnology (2018) 9:44 https://doi.org/10.1186/s40104-018-0259-8 REVIEW Open Access Endometrial response to conceptus- derived estrogen and interleukin-1β at the time of implantation in pigs 1* 1,2 1,3 1 1 Hakhyun Ka , Heewon Seo , Yohan Choi , Inkyu Yoo and Jisoo Han 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 Background histotrophs and immune modulation for conceptus devel- A high rate of embryonic mortality occurs in all mammals. opment and placentation in the endometrium [2, 3]. In pigs, embryonic mortality before day (d) 30 of pregnancy During the peri-implantation period, the porcine con- can be up to 40%, and most embryonic losses occur during ceptus undergoes dramatic morphological changes from the peri-implantation period . An understanding of the spherical (3 to 10 mm in diameter) to ovoidal to tubular cellular and molecular mechanisms underlying conceptus– (10 to 50 mm in length) and then to filamentous forms endometrial interactions for the establishment of pregnancy (100 to 800 mm in length) as it secretes a variety of fac- is essential to reducing embryonic mortality. In pigs, the es- tors, including estrogens and cytokines, interleukin-1β2 tablishment of pregnancy is a complex process that requires (IL1B2), interferon-γ (IFNG), and IFN-δ (IFND), into well-coordinated interactions between the implanting con- the uterine lumen. It also migrates in the uterine lumen ceptus (embryo/fetus and associated extraembryonic mem- for appropriate embryo spacing and uses noninvasive branes) and the maternal uterus. This leads to an extended implantation to develop a true epitheliochorial placenta lifespan for the corpus luteum (CL) for continued produc- [2, 4, 5]. Meanwhile, the endometrium, which is affected tion of progesterone in the ovary and the secretion of by progesterone from the ovary during this period, prepares for conceptus implantation by producing histotrophs such as growth factors, ions, amino acids, monosaccharides, en- * Correspondence: firstname.lastname@example.org zymes, nutrient binding proteins, and extracellular matrix Department of Biological Science and Technology, Yonsei University, Wonju (ECM) proteins and by changing the gene expression, cellu- 26493, Republic of Korea lar morphology, and maternal immune environment to Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ka et al. Journal of Animal Science and Biotechnology (2018) 9:44 Page 2 of 17 allow the adhesion of the conceptus trophectoderm to the Estrogen endometrial epithelial cells and the development of an allo- Plasma estrogen concentrations in pigs increase prior to geneic fetus [3, 6, 7]. estrus and decrease on the day of estrus. During the es- Conceptus-derived factors affect various aspects of trous cycle, the mean plasma concentrations of estradiol endometrial function. Estrogens and IL1B2 are produced are less than 20 pg/mL until d 16 or d 17, and then they by the elongating conceptus on d 10–12 of pregnancy increase to their maximal concentration of 50 pg/mL 1 [2, 3]. Estrogens signal a maternal recognition of preg- or 2 d prior to estrus [25, 26]. Between d 12 and d 15 of nancy in pigs because they act on a redirection of endo- the estrous cycle, estrone and estradiol concentrations metrial prostaglandin (PG) F secretion from the are elevated in cyclic pigs . There is no difference in 2α uterine vasculature to the uterine lumen to protect the plasma estradiol concentrations between cyclic and corpus luteum and ensure continued production of pro- pregnant pigs for the first two weeks after the onset of gesterone [2, 8]. Estrogens also affect the expression of estrus , but the estradiol concentrations in the endometrial genes involved in PG production, calcium utero-ovarian vein between d 12 and d 17 are higher in movement, and IFN signaling [2, 9–11]. The direct effect pregnant pigs than in cyclic pigs  (Fig. 1). Estrogen of conceptus-derived IL1B2 at the maternal–conceptus concentrations in the uterine lumen are estimated by interface is not fully understood, but it has been shown analyzing uterine flushing from pigs [27, 29, 30]. In cyc- that IL1B induces the expression of many endometrial lic pigs, estrone and estradiol contents are constant at genes related to PG production and transport and the 200 to 300 pg between d 6 and d 16 of the estrous cycle, IL1B and IFN signaling pathways [10, 12, 13]. On d 12–20 and estrone content increases to 1,000 pg on d 18. In of pregnancy, the conceptus trophectoderm produces pregnant pigs, estradiol content is about 300 pg until significant amounts of IFN-γ (IFNG) and IFN-δ (IFND) d 10 after the onset of estrus, at which point it increases with the highest antiviral activity on d 14–d16 ofpreg- to about 1,400 pg between d 10 and d 12, decreases to nancy in pigs [14–16]. IFNG is the predominant type II d 15, and then increases again on d 18. The estrone con- IFN, comprising approximately 75% of antiviral activity tent in pregnant pigs also increases to 1,500 pg on d 8, in uterine flushings, and IFND is a novel type I IFN in decreases to d 12, then increases slowly to 3,700 pg on pigs [14–16]. Unlike IFN-τ (IFNT), a type I IFN pro- d18 . Total recoverable estrone, estradiol, and estriol duced by the conceptus and acting as a signal for mater- in cyclic pigs do not change, whereas in pregnant pigs, nal recognition of pregnancy by preventing endometrial total estrone and estradiol increase about 6-fold from d 10 production of luteolytic PGF in ruminants , IFND to d 12. Total recoverable estrone sulfate and estradiol 2α and IFNG do not have an anti-luteolytic effect in pigs sulfate also increase from d 10 to d 12 in pregnant pigs . IFNs secreted by the conceptus trophectoderm in- . The increase in estrogen concentrations in the duce many IFN-stimulated genes and class I and II uterine lumen of pregnant pigs reflects estrogen production major histocompatibility complex (MHC) molecules in by the conceptus, which converts androgens to estrogens the endometrium [19–22], but detailed function of IFNs [32, 33]. Catechol estrogens (2- and 4-hydroxyestradiol) are at the maternal-conceptus interface is not fully under- also converted from estradiol by porcine conceptuses stood in pigs. during early pregnancy [34, 35]. Several recent reviews have well described the events and the molecules involved in the establishment of preg- Progesterone nancy during the peri-implantation period in pigs [2, 9, Progesterone is secreted by the CL, adrenal cortex, and 23, 24]. The present review highlights current informa- placenta and is necessary for implantation, the regulation tion, focusing on the roles of conceptus-derived estrogen of uterine development, uterine secretion, mammary and IL1B during the implantation period in pigs. gland development, and lactogenesis. Plasma progesterone concentrations increase rapidly from less than 1 ng/mL Estrogen, progesterone, and their teceptors on the day of estrus to about 30 ng/mL on d 12 and d 14 during the estrous cycle and early pregnancy in both cyclic and pregnant pigs. In cyclic pigs, progester- The estrous cycle and establishment and maintenance of one concentrations decrease rapidly from d 15 to less than pregnancy are regulated by the orchestrated actions of vari- 1 ng/mL on d 18 of the estrous cycle [25, 26]. This de- ous hormones from hypothalamus, pituitary, ovary, uterus crease in progesterone concentrations in cyclic pigs results and conceptus. These hormones include gonadotropin- from CL regression induced by PGF from the uterine 2α releasing hormone (GnRH) from the hypothalamus, follicle endometrium. In pregnant pigs, progesterone concentra- stimulating hormone (FSH) and luteinizing hormone (LH) tions decrease slowly from d 14 to d 30, reaching 10–20 from the pituitary, estrogen and progesterone from the ng/mL, and then remain fairly constant throughout preg- ovary, estrogen from the conceptus and PGF from the nancy until near term [25, 36](Fig. 1). Progesterone is also 2α uterus (Fig. 1). present in the lumen of the uterus [27, 30]. Progesterone Ka et al. Journal of Animal Science and Biotechnology (2018) 9:44 Page 3 of 17 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 (PGF) from the endometrium. b. During pregnancy estrogen 2α concentrations decrease from estrus, maintain low concentrations with brief increases on around d 12 and d 25–d30ofpregnancy, andincreaseprior 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 in uterine flushing increases from d 14 to d 16 and then regulation and function of ESR2 is not fully understood in decreases to d 18 of pregnancy . Concentrations of pigs [39, 40]. The presence of the membrane-associated pregnenolone, progesterone, and pregnenolone sulfate in estrogen receptors including membrane-bound ESR1 and uterine flushing between d 9 and d 15 are higher in preg- G-protein coupled estrogen receptor 1 (GPER1), which nant pigs than in cyclic pigs . activate non-genomic actions of estrogen, has been de- scribed in various tissue and cell types in several species Receptors for estrogen and progesterone [41, 42]. However, the expression of membrane-bound Estrogen and progesterone actions in the uterus are pri- ESR1 or GPER1 has not been determined in the porcine marily mediated through estrogen receptor-α (ESR1) endometrium. and progesterone receptor (PGR), respectively. In pigs, PGR expression in the porcine uterus during the es- the expression of ESR1 and PGR changes depending on trous cycle and pregnancy has been determined [43–45]. the estrous cycle and pregnancy. Nuclear ESR1 concen- The endometrial PGR concentrations are highest be- trations increase from estrus (d 0) to d 12 of the estrous tween d 0 and d 5 of the estrous cycle, decrease by d 10 cycle and then decrease by d 15. Endometrial ESR1 and d 11, and then remain low until the next proestrus mRNA expression is highest on d 10, declines by d 15, phase. This pattern is the same in pregnant pigs until and then increases by d 18 in cyclic and pregnant pigs. d 11 to d 12, and low abundance of endometrial PGR However, in pregnant pigs ESR1 remains suppressed expression are maintained until d 85 of pregnancy. after d 18 of pregnancy . In cyclic and pregnant pigs, PGR protein is localized in LE and GE cells and the ESR1 proteins are localized in luminal epithelial (LE) stroma between d 0 and d 5 with strong intensity. and glandular epithelial (GE) cells and the stroma at es- PGR in LE and GE cells declines from d 7, is not de- trus. ESR1 is detectable in LE and GE cells between d 5 tectable in LE or superficial GE cells on d 12, and and d 15 of the estrous cycle and pregnancy, whereas then increases by d 18 in cyclic pigs. In pregnant ESR1 in the stroma decreases markedly during this pigs, the pattern of PGR localization is the same as period. Between d 10 and d 12, strong ESR1 staining is for cyclic pigs until d 12, but PGR staining in epithe- detectable in LE and GE cells. On d 15, ESR1 staining lial cells does not increase until the late stage of decreases in LE and GE cells and then increases in LE pregnancy. Stromal PGR is detectable throughout the and GE cells and the stroma on d 18 of the estrous cycle estrous cycle and pregnancy, even though staining in- in cyclic pigs, but remains low after d 18 in pregnant tensityislower betweend5and d15ofthe estrous pigs . Estrogen receptor-β (ESR2), a subtype of nu- cycle and pregnancy than at estrus. Stromal PGR in- clear estrogen receptors, is expressed in LE and GE cells creases on d 18 in cyclic pigs but not in pregnant in the endometrium during the estrous cycle and preg- pigs. PGR is localized to the myometrium throughout nancy and in conceptus trophectoderm on d 12 , but all day of the estrous cycle and pregnancy. Ka et al. Journal of Animal Science and Biotechnology (2018) 9:44 Page 4 of 17 The down-regulation of PGR in uterine LE cells during the migration of the endoderm at the tip of the epiblast the implantation period is a phenomenon common to . It has been proposed that epiblast-derived fibro- several mammalian species, including pigs, ruminants, blast growth factor 4 (FGF4) is involved in communica- humans, and mice, indicating that loss of PGR in the tion with the trophectoderm cells by binding to FGF uterine epithelial cells is a prerequisite for uterine recep- receptor 2 (FGFR2) and activating the mitogen-activated tivity to implantation, gene expression by uterine epithe- protein kinase (MAPK) signaling pathway in the troph- lial cells, and transport of molecules in the uterine ectoderm cells of the spherical and ovoidal conceptuses lumen for a developing conceptus . Because proges- prior to the elongation process . FGF4 treatment of terone profoundly affects uterine receptivity for implant- porcine trophectoderm cells in vitro induces cell migra- ation, this paradox could be explained by stromal cell- tion and activates the protein kinase B (also known as derived growth factors known as progestamedins that the AKT) signaling pathway . In addition, bone mor- are produced and released from uterine stromal and phogenetic protein 4 from extraembryonic mesoderm is myometrial cells and express PGR through the action of also involved in the cellular reorganization of trophecto- progesterone [47, 48]. However, the presence of several derm cells during conceptus elongation . Further membrane progesterone receptors, progesterone mem- growth and development of the conceptus during the brane component 1 (PGRMC1) and PGRMC2, and pro- peri-implantation period is stimulated by many growth gestin and adipoQ receptor (PAQR) 5 to PAQR9, which factors and cytokines produced by the endometrium, in- are all G-protein-coupled receptors, has been shown in cluding epidermal growth factor (EGF) [64, 65], FGF7 reproductive tissues and other tissues in humans, mice, , insulin-like growth factor-1 (IGF1) , interleukin and bovines [49–51]. Our study also shows that endo- 6 (IL6), leukemia inhibitory factor , and transforming metrial epithelial cells express PGRMC1, PGRMC2 and growth factor beta (TGFB) . PAQRs during the estrous cycle and pregnancy in pigs (Kim and Ka, unpublished data), suggesting that those Conceptus adhesion to the endometrium membrane progesterone receptors in endometrial epi- The adhesion cascade for the implantation of a porcine thelial cells could be responsible for progesterone ac- conceptus to the maternal endometrium proceeds tions during the progesterone-dominant period of the through a sequence of events: 1) hatching of the blastocyst estrous cycle and pregnancy. from the zona pellucida, 2) precontact and orientation of the conceptus to the uterine LE cells, 3) apposition of the Conceptus development during early pregnancy trophectoderm to the uterine LE cells, and 4) adhesion of In pigs, following fertilization, cleavage of the embryo the trophectoderm to the uterine LE cells [2, 59]. Al- occurs in the oviduct. Four-cell embryos enter the uterus though the initial early stages of implantation are common approximately 48 h after ovulation, develop to the to all species, the invasion of the trophectoderm across blastocyst stage by d 5, and then shed the zona pellucida the uterine LE cells and stroma does not occur in pigs, on d 6 or d 7 [52–54]. Blastocysts measure less than 3 which uses non-invasive implantation and a true epithelio- mm in diameter until d 10 with considerable variation chorial type of placenta . In pigs, attachment of the . During this period, the blastocysts secrete estrogen conceptus to the uterine epithelium initiates around d 13  and migrate in the uterus for spacing prior to im- to d 14, and full attachment is completed after d 18 . plantation [53, 55, 56]. Shortly before implantation, be- Conceptus trophectoderm cells during this period are tween d 11 and d 12, porcine blastocysts undergo apposed closely to the uterine epithelium, and the embry- dramatic morphological changes, as described above. In onic disc region is rigidly attached to the uterine epithe- contrast, morphological elongation of blastocysts does lium, with more distal regions of the chorion separated not occur in rodents or primates, and extraembryonic from the luminal surface . membranes are formed after implantation [57–59]. Dur- The endometrial LE cells undergo morphological and ing the peri-implantation period, porcine conceptuses functional changes during the adhesion phase. The secrete a variety of molecules, such as estrogen, cyto- apical-basal polarity of the LE cells decreases as the col- kines, PGs, growth factors, and proteases [2, 3]. umnar epithelium with microvilli changes into cuboidal The initial elongation from spherical blastocysts to epithelium with a loss of microvilli . Tight junctions filamentous conceptuses is achieved by cellular remo- between endometrial LE cells are in the basolateral re- deling, not by cellular hyperplasia because the mitotic gion. In addition, the nuclei of LE cells become larger index and DNA contents of the conceptuses do not and more vesicular, and the cytoplasm is less dense and change during elongation . The conceptus elong- accumulated, with glycogen droplets at the basal side ation process includes changes in microfilament orienta- [71–73]. The apical surfaces of the LE cells are covered tion by rearrangement of the actin cytoskeleton [60, 61] with a thick filamentous glycocalyx during the attachment and junctional complexes of trophectoderm cells and phase [71, 73]. Mucin 1 (MUC1), a transmembrane mucin Ka et al. Journal of Animal Science and Biotechnology (2018) 9:44 Page 5 of 17 glycoprotein in glycocalyx, is down-regulated during the cells and the αvβ3 on pUE cells, suggesting that SPP1 implantation period in pigs and ruminants [74, 75]. acts as a bidirectional bridging ligand during conceptus MUC1 is known to act as an anti-adhesive component be- implantation . The expression and function of SPP1 tween LE cells and trophectoderm cells by sterically inhi- in the adhesion cascade at the uterine-conceptus inter- biting cell-cell and cell-ECM binding [58, 76]. Thus, it is face has been shown in several species, including suggested that down-regulation of MUC1 results in ex- humans, mice, rabbits, and sheep, suggesting that the posure of low-affinity carbohydrate ligand binding mole- SPP1-mediated cell adhesion process for conceptus im- cules such as selectins and galectins as well as a variety of plantation is conserved across species . Furthermore, cell adhesion molecules, including cadherins and integrins latency-associated peptide (LAP), part of the TGFB com- . In humans and rabbits, the pattern of MUC1 expres- plex, binds to integrin receptors αvβ1, αvβ3, and αvβ5at sion in endometrial epithelial cells is somewhat different: the apical surfaces of uterine LE and trophectoderm cell MUC1 expression in LE cells increases during the recep- attachments, suggesting that LAP-integrin complexes tive phase but is locally reduced at the attachment sites by also promote conceptus attachment . Overall, these cell surface proteases (sheddases) derived from the blasto- findings indicate that in pigs the cell adhesion cascade cyst or blastocyst-induced paracrine factors [58, 77]. It is between endometrial LE and conceptus trophectoderm believed that progesterone induces epithelial MUC1 ex- cells during the implantation period is a complex pression, and down-regulation of PGR causes the dis- process that involves a variety of adhesive factors. appearance of MUC1 on the uterine LE and superficial GE cells for the establishment of uterine receptivity to im- Maternal recognition of pregnancy plantation . Progesterone is required for pregnancy maintenance be- Among many cell adhesion molecules, the roles of in- yond the estrous cycle in most mammals, including pigs, tegrin and several ECM proteins have been well studied ruminants, rodents, and primates . To sustain proges- in the adhesion process between endometrial LE and terone production from the CL and maintain a pregnancy, trophectoderm cells in domestic animal species, includ- species use a variety of strategies to abrogate luteolysis. In ing pigs and sheep [23, 76]. Integrins are heterodimeric general, the conceptus produces antiluteolytic signals that glycoprotein receptors composed of non-covalently prevent the secretion or action of PGF (pigs and rumi- 2α linked α and β subunits that bind to the Arg-Gly-Asp nants) or that are directly luteotrophic to keep the CL se- (RGD) and non-RGD amino acid sequences of various creting progesterone (primates). ECM components and cell adhesion molecules . The Maternal recognition of pregnancy is usually defined as activation of integrin receptors in LE and trophectoderm the rescue of the CL from undergoing luteolysis, although cells in the implantation adhesion process causes cyto- maternal function is altered as early as the period when skeletal reorganization and changes in gene expression the embryo is in the oviduct, and the mechanism to estab- for adhesion, migration, and invasion . In pigs, uter- lish pregnancy and maintain CL function varies among ine LE cells express integrin subunits α1, α3, α4, α5, αv, species. The presence of a maternal recognition signal β1, β3, and β5; trophectoderm cells express α1, α4, α5, from pig conceptuses was predicted by studies on the ef- αv, β1, and β3; and αvβ1, αvβ3, αvβ5, α4β1, and α5β1 fect of flushing conceptuses from uterine horns on various are localized at the attachment sites between uterine LE days of pregnancy. Removal of conceptuses from the and trophectoderm cells . Secreted phosphoprotein uterus between d 4 and d 10 does not affect the CL life- 1 (SPP1; also known as osteopontin), fibronectin, and span , whereas flushing conceptuses from the uterus vitronectin, which are ECM protein ligands for integrin on or after d 12 increases the inter-estrous interval by 3 or receptors, are expressed in the endometrium at the time more days . Therefore, signals for maternal recogni- of LE and trophectoderm cell adhesion [78–80]. SPP1 is tion of pregnancy in pigs are produced by conceptuses on known to bind to αvβ1, αvβ3, αvβ5, and α4β1; fibronec- about d 12 for the maintenance of pregnancy. Perry and tin interacts with α4β1; and vitronectin binds mainly to coworkers first demonstrated that estrogen was produced αvβ3[23, 78]. The expression of SPP1 in the endomet- by conceptuses during the period of maternal recognition rium is particularly induced by estrogen of conceptus of pregnancy in pigs . There is considerable evidence origin at the uterine LE cells juxtaposed to the concep- for the antiluteolytic effects of estrogen . Administra- tus trophectoderm, beginning around d 12 and extend- tion of exogenous estrogen in cyclic pigs between d 11 ing to all LE cells by d 20. High abundance of SPP1 and d 15 extends the inter-estrous interval and decreases expression is maintained at the maternal-conceptus the concentration, peak height, and pulse frequency of interface throughout pregnancy [79, 81, 82]. In vitro PGF release from the uterus . Estrogen treatment on 2α analysis using porcine trophectoderm (pTr) cells and d 9.5, d 11, d 12.5, d 14, d 15.5 or d 14-16 of the estrous uterine endometrial epithelial (pUE) cells has shown that cycle results in an inter-estrous interval of about 30 d . SPP1 binds directly to the αvβ6 integrin subunits of pTr Daily treatment between d 11 and d 15 or two period Ka et al. Journal of Animal Science and Biotechnology (2018) 9:44 Page 6 of 17 treatments on d 11 and d 14 to d 16, corresponding to the sulfur-conjugated estrogens (estrone sulfate, estradiol sul- pattern of estrogen production by conceptuses, prolongs fate and estriol sulfate) are observed in uterine fluids [31, CL function beyond d 60. The uterine content of total re- 96]. Estrogen sulfotransferase produced by the endomet- coverable estrogens (estrone, estradiol, and estriol) in rium is responsible for the conversion of free estrogens to pregnant pigs increases on d 11 to d 12, declines on d 13 conjugated estrogens [96, 97]. Catechol estrogens, 2- and to d 14, and then increases after d 14 of pregnancy, 4-hydroxyestradiols, are also produced by the elongating whereas in cyclic pigs, estrogen concentration does not in- conceptuses, which exhibit estrogen-2-hydroxylase and crease before d 15 of the estrous cycle when preovulatory estrogen-4-hydroxylase activity [34, 35, 98]. In mice, cat- follicles are present [30, 31]. echol estrogens are involved in the activation of dormant The current theory of maternal recognition of preg- blastocysts for implantation in delayed-implanting mice nancy in the pig is the endocrine-exocrine theory . It . Although it has been reported that catechol estrogen suggests that uterine endometrial cells differentially se- induces uterine vasodilation when infused into the utero- crete PGF or luteolysin, depending on estrogen se- artery  and changes PG production in cultured en- 2α creted by conceptuses. In cyclic pigs, endometrial PGF dometrial tissues in vitro [101, 102], the role of catechol 2α is secreted into the uterine vasculature, which is trans- estrogens in the implantation process is not fully under- ported to the ovary to cause luteolysis on d 15 to d 16 of stood in pigs. the estrous cycle (endocrine). However, in pregnant pigs, the uterine endometrium’s response to estrogen pro- Growth factor expression duced by conceptuses from d 11 and d 12 to d 15 is to The onset of estrogen production by the implanting con- secrete PGF into the uterine lumen, where it is seques- ceptus coincides with the time of maternal recognition 2α tered to exert its biological actions in the uterus or be of pregnancy in pigs, and estrogen acts as a maternal metabolized to prevent luteolysis (exocrine) [2, 8]. In- pregnancy recognition signal [2, 8]. Conceptus-derived deed, PGF concentration in the utero-ovarian vein is estrogens regulate the expression of a variety of genes 2α significantly higher in cyclic pigs on d 13 to d 17 than in involved in cell proliferation, adhesion, migration, PG pregnant pigs . This theory is also supported by a production, ion and nutrient transport, and immune re- report that in cyclic pigs, total recoverable PGF per uter- sponse in an endometrium primed with progesterone 2α ine horn was 1.98 ng on d 11, 210.2 ng on d 17, and 66.2 during the implantation period. Many growth factors, in- ng on d 19 of the estrous cycle, whereas in pigs treated cluding connective tissue growth factor , EGF, with estrogen between d 11 and d 15, total recoverable heparin-binding EGF [64, 104, 105], FGF1, FGF2 , PGF was 1.9 ng, 4,144.3 ng, and 4,646.7 ng on the same and FGF7 , IGF1 and IGF2 , TGFB1, TGFB2, 2α respective days . PGE concentrations in the uterine and TGFB3 , and vascular endothelial growth factor lumen also increase on d 11 to d 14 in pigs . In , are expressed by the endometrium and conceptus contrast to PGF ,PGE could have a luteotrophic during the implantation period and regulate cell division, 2α 2 effect and protect the CL against the luteolytic action proliferation, morphogenesis, and differentiation . of PGF [89, 90]. Another possible mechanism for Among them, the most well-studied growth factors in- 2α preventing luteolysis during maternal recognition of duced by conceptus estrogen during early pregnancy are pregnancy is an increase in the PGE :PGF ratio in IGF1 and FGF7. The endometrial transcripts and pro- 2 2α response to estrogen secreted by conceptuses in the teins of IGF1 secreted into the uterine lumen are great- uterus [90–94]. Therefore, PG synthesis and secretion est on d 12 of pregnancy, coincident with maximal appear to be critical and tightly regulated to modulate estrogen production by the conceptus in pigs [108, 111, luteolysis and maternal recognition of pregnancy in the 112]. IGF1 expression is localized in the LE, GE, endo- uterine endometrium in pigs. thelial, and vascular smooth muscle cells of the endo- metrium and conceptus trophectoderm ; IGF2 is Conceptus estrogens and their role in localized in the LE and GE; and IGF-binding protein 2 endometrial function (IGFBP2) is localized in epithelial and stromal cells Conceptus estrogens . Estrogen injection into ovariectomized pigs and It is well established that the elongating conceptus pro- acute estrogen treatment of pigs on d 11 of the estrous duces estrogens at the time of implantation in pigs, as cycle increases the endometrial expression and secretion stated previously [2, 32]. The expression of 17α- of IGF1 . IGF receptors and IGFBPs regulating the hydroxylase (CYP17A1) and aromatase (CYP19A1), en- bioavailability of IGFs are expressed by endometrial and zymes responsible for the synthesis of estrogens, is de- conceptus tissues, and IGFBPs are present in the uterine tectable in the trophectoderm cells of spherical to lumen during early pregnancy [67, 111, 114, 115]. It has filamentous conceptuses on d 11 and d 12 [67, 95]. Un- been shown that IGF1 and IGF2 increase the prolifera- conjugated estrogens (estrone, estradiol, and estriol) and tion of porcine endometrial GE cells in vitro . In Ka et al. Journal of Animal Science and Biotechnology (2018) 9:44 Page 7 of 17 addition, it is proposed that IGF1 acts through the stimu- endometrium increases dramatically in LE cells at the time lation of CYP19A1 expression for conceptus estrogen pro- of conceptus implantation. Endometrial LE expression of duction based on the overlapping expression patterns of SPP1 is maintained until late pregnancy, and SPP1 expres- CYP19A1 in the conceptus and IGF concentrations in the sion in GE cells is first detected on d 35 and increases uterine lumen . thereafter . Estrogen induction of endometrial SPP1 FGF7, also known as keratinocyte growth factor, is a expression is evidenced by the finding that SPP1 expres- member of the heparin-binding FGF family and stimu- sion is first detected in endometrial LE cells in direct con- lates epithelial growth and differentiation . Because tact with the implanting conceptus and expands to all LE FGF7 usually originates from mesenchymal cells and cells by d 20. Also, injection of estradiol into cyclic pigs to mediates epithelial–mesenchymal interactions in many induce pseudopregnancy increases endometrial SPP1 ex- tissues, including the reproductive tract [117, 118], it pression [79, 81]. Immunoreactive SPP1 proteins are was hypothesized that FGF7 is expressed in endometrial found in endometrial LE and GE cells and trophectoderm stromal cells and regulates epithelial cell function by act- cells, as well as in uterine flushing [79, 81]. Because SPP1 ing as a progestamedin in the uterine endometrium dur- directly binds to the αvβ6 integrin subunit of pTr cells ing the progesterone-dominant period. Contrary to that and the αvβ3 on pUE cells, as noted previously, and be- hypothesis, FGF7 in the porcine uterus is expressed in cause SPP1 can also interact with other integrin receptors, endometrial epithelial cells, predominantly in LE cells such as α5β1, αvβ1, αvβ5, αvβ6, α8β1, α4β1, α9β1, and during early pregnancy and in GE cells during late preg- α4β7, it is suggested that SPP1 acts as a bidirectional nancy . FGF7 expression is abundant between d 12 bridging ligand to stimulate cell adhesion, migration, and and d 15 of the estrous cycle and pregnancy, with the proliferation for conceptus implantation and placentation greatest abundance on d 12 of pregnancy; FGF7 protein [80, 121]. is also detectable in uterine flushing on d 12 of both the estrous cycle and pregnancy . Treatment of endo- Calcium secretion and the expression of calcium- metrial explants with estradiol and estradiol injection regulatory molecules into ovariectomized pigs increase the expression of Calcium plays critical roles in a variety of physiological FGF7 in the endometrium, indicating that the dramatic processes, including bone formation, muscle contraction, increase in endometrial FGF7 expression is induced by and neuronal excitability. At the cellular level, it regu- estrogen of conceptus origin [66, 119]. The FGF7 recep- lates cell growth, proliferation, differentiation, and death tor 2IIIb (FGFR2IIIb) is expressed in both the endomet- by mediating many cell functions, such as intracellular rial epithelium and conceptus trophectoderm . signaling and cell adhesion [122, 123]. In pigs, it is well Treatment of FGF7 with pTr cells, a trophectoderm cell established that conceptus estrogen induces endometrial line derived from d 12 porcine conceptuses, increases calcium secretion into the uterine lumen during the im- [ H]thymidine incorporation, phosphorylation of FGFR2IIIb plantation period; endometrial calcium secretion in- and extracellular signal-regulated kinases 1/2 (ERK1/2), creases significantly as the conceptuses elongate from and expression of urokinase-type plasminogen activator tubular to filamentous conceptus stage and decreases by (PLAU), a marker for differentiation of porcine trophecto- d14[29, 88], and endometrial calcium secretion in- derm cells, indicating that FGF7 acts on the proliferation creases in response to estrogen injection into cyclic pigs and differentiation of the conceptus trophectoderm in a at 12 h, peaks by 24 h, and declines by 48 h [124, 125]. paracrine manner . The role of FGF7 in endometrial Although the mechanism underlying estrogen-induced epithelial cells is not yet understood. calcium release in the endometrium is not fully under- stood at the cellular or tissue level in pigs, the expres- 2+ SPP1 expression sion of calcium extrusion molecules, ATPase Ca The adhesion process between the endometrial epithelium transporting plasma membrane (also called plasma and conceptus trophectoderm requires various cell adhe- membrane calcium ATPase), solute carrier family 8 (also sion molecules to be expressed and produced by the endo- called sodium/calcium exchanger), and solute carrier metrium and trophectoderm . Among the many cell family 24 (also called potassium-dependent sodium/cal- adhesion molecules, SPP1 is the best-characterized mol- cium exchanger), in the endometrium indicates that they ecule to be induced by conceptus-derived estrogen. SPP1, could be involved in mediating the extrusion of calcium an ECM protein, is a highly phosphorylated acidic glyco- ions across the plasma membranes of cells in the endo- protein that stimulates cell-cell adhesion, increases cell- metrium . During early pregnancy, the expression ECM communication, and promotes cell migration . of stanniocalcin 1 (STC1) has been shown in endomet- Endometrial secretion of SPP1 has been shown in several rial LE cells, induced by ovarian progesterone and con- species, including pigs, sheep, humans, nonhuman pri- ceptus estrogen , suggesting the possibility of a role mates, and rodents . In pigs, SPP1 expression in the for STC1 in endometrial calcium secretion. It is also Ka et al. Journal of Animal Science and Biotechnology (2018) 9:44 Page 8 of 17 likely that calcium secretion into the uterine lumen is LPAR3 induction . The production of LPAs is medi- regulated through a paracellular mechanism at the endo- ated by ectonucleotide pyrophosphatase/phosphodiesterase metrial epithelial tight junctions, which play a role in the 2 (ENPP2; also called autotaxin), a key enzyme with lyso- permeability of the paracellular barrier and are differen- phospholipase D (lysoPLD) activity . In pigs, the uter- tially expressed in endometrial epithelial cells during ine endometrium, specifically GE cells, and the conceptus early pregnancy in pigs (Choi and Ka, unpublished data). trophectoderm express ENPP2, and lysoPLD activity is de- At the time of implantation in pigs, estrogen also in- tected in uterine flushing from d 12 of both the estrous creases endometrial expression of transient receptor po- cycle and pregnancy, with higher concentrations on d 12 of tential cation channel subfamily V member 6 (TRPV6), a pregnancy suggesting the involvement of conceptus signals calcium ion channel responsible for the absorption of in increased lysoPLD activity . In mice, deletion of the calcium ions into the cell, and S100 calcium-binding Lpar3 gene causes delayed implantation, aberrant embryo protein G (S100G, also called calbindin-D9k), an intra- spacing, hypertrophic placentas, and embryonic death, cellular calcium transport protein [128, 129]. The ex- along with the reduction of PG-endoperoxide synthase 2 pression of TRPV6 and S100G has been detected in (PTGS2) expression, which results in PGE and PGI secre- 2 2 endometrial LE and trophectoderm cells during early tion in the endometrium . In the pig uterus, LPA in- pregnancy, indicating that calcium ions are needed for creases PTGS2 expression in the endometrium . In a epithelial and trophectoderm cell functions during the cultured porcine trophectoderm cell line, pTr, LPA acti- implantation period . Estrogen also increases endo- vates the ERK1/2 and p90 ribosomal S6 kinase signaling metrial calcium absorption in cultured porcine endomet- pathway and increases cell proliferation and migration and rial explant tissues, most likely through TRPV6 (Choi the expression of PTGS2 and PLAU . Thepresenceof and Ka, unpublished data). The cell adhesion process be- LPA in uterine flushing and LPA-induced increases in cell tween endometrial epithelial cells and trophectoderm proliferation and the production of PGE and PGF in 2 2α cells during the implantation period involves many cell trophectoderm cells have been shown in sheep . Over- adhesion molecules, including integrins, cadherins, all, these findings indicate that in pigs, conceptus estrogen selectins, and ECM proteins such as SPP1, which all re- activates the production of LPA and increased endometrial quire calcium ions for appropriate functional activity LPAR3 expression to regulate endometrial PG production and are present at the attachment sites at the maternal– and the proliferation and differentiation of conceptus conceptus interface in pigs [23, 76]. In addition, it has trophectoderm cells (Fig. 2). Furthermore, because embryo been shown that the cell adhesion process activates spacing is altered in Lpar3-null mice , it is likely that intracellular calcium signaling. Interactions between the migration and spacing of pig blastocysts, which are crit- endometrial epithelial cells and trophoblastic cells in ical events preceding implantation and placentation, are vitro increase calcium influx and intracellular calcium also regulated by LPA in pregnant pigs. Recently, it has signaling in endometrial epithelial cells in humans [130, been reported that CYP19A1-null porcine embryos elong- 131]. Thus, it is likely that calcium ions secreted by the ate normally but show lowered estrogen production on endometrium and absorbed into endometrial epithelial d 14 postestrus, suggesting that estrogen synthesis is not and conceptus trophectoderm cells play a critical role in essential for conceptus elongation . the cell adhesion process. PG synthesis Regulation of LPA-LPAR3 signaling PGs derived from the conceptus or endometrium play Lysophosphatidic acids (LPAs), simple phospholipid- essential roles in implantation, decidualization, and con- derived mediators, induce many growth factor-like bio- ceptus development at the maternal-conceptus interface logical effects, such as cell proliferation, survival, migra- in mammals [140, 141]. In ruminants, IFNT, the mater- tion, and differentiation, via G protein-coupled receptors nal pregnancy recognition signal from the conceptus, in various cell types and are found in various body suppresses the pulsatile release of endometrial PGF re- 2α fluids, including serum, saliva, seminal plasma, and fol- quired for luteolysis by silencing endometrial ESR1 and licular fluid [132, 133]. Our study in pigs showed that OXTR expression, although basal concentrations of LPAs (LPA16:0, LPA18:0, LPA18:1, LPA18:2, and LPA20:4) PGF are produced in the endometrium during the im- 2α are detectable in uterine lumen, with higher amounts of plantation period, and PG content in the uterine lumen LPA16:0, LPA18:0, and LPA18:2 on d 12 of pregnancy than is much higher during early pregnancy than during the on d 12 of the estrous cycle. LPA receptor 3 (LPAR3) is estrous cycle [46, 142]. Conceptus estrogen in pigs in- expressed in endometrial epithelial cells, with the greatest creases the production of PGE and PGF in the por- 2 2α abundance on d 12 of pregnancy. In addition, endometrial cine endometrium [10, 91, 124, 143]. Synthesis of PGs expression of LPAR3 is increased by estradiol, indicating involves the sequential actions of several enzymes, in- that conceptus estrogen is responsible for endometrial cluding phospholipase A , PG-endoperoxide synthase 1 2 Ka et al. Journal of Animal Science and Biotechnology (2018) 9:44 Page 9 of 17 PG activity during the implantation process includes increased endometrial vascular permeability, endometrial gene expression, and conceptus elongation in many spe- cies [94, 140, 141, 150]. In sheep, blocking PG synthesis in the conceptus and endometrium by an intrauterine infusion of meloxicam, a PTGS inhibitor, from d 8 to d 14 post-mating suppresses conceptus elongation on d 14 post-mating, indicating that PGs are essential for conceptus elongation . PGs also regulate the expression of elong- ation- and implantation-related genes, including GRP, IGFBP1, LGALS15,and HSD11B1, in the endometrial epi- thelium during the implantation period in sheep . In pigs, an intrauterine infusion of PGE directly inhibits PGF -induced regression of the CL in a dose-dependent 2α manner, suggesting that PGE has a luteotrophic effect that protects the CL against the luteolytic action of PGF [89, 2α 90, 151]. Recently, Kaczynski and coworkers showed that in pigs, PGF induces endometrial expression of vascular 2α endothelial growth factor-A, biglycan, matrix metallopro- tease 9, IL1A, and TGFB3, suggesting that PGF is in- 2α volved in angiogenesis and tissue remodeling during early pregnancy . Nevertheless, the detailed functions of PGs at the maternal-conceptus interface in pigs still need further study. Regulation of IFN signaling Conceptus estrogen is also critical to the activation of Fig. 2 Working model of the role of lysophosphatidic acid (LPA) at the endometrial expression of IFN signaling molecules the maternal-conceptus interface in pigs. Estrogen of conceptus during early pregnancy. Signal transduction and activa- origin induces endometrial epithelial expression of LPA receptor 3 tor of transcription 1 (STAT1) is a key molecule involved (LPAR3), and ectonucleotide pyrophosphatase/phosphodiesterase 2 in the activation of IFN-stimulated genes (ISGs) in re- (ENPP2) activates endometrial production of LPA. LPAs secreted into sponse to type I and II IFNs . STAT1 expression in the uterine lumen act on endometrial luminal (LE) and glandular epithelial (GE) cells to increase the expression of prostaglandin (PG)- the porcine endometrium is detected in LE cells on d 12 endoperoxide synthase 2 (PTGS2), which in turn acts on the of pregnancy and in stromal cells from d 15 of preg- production of PGF and PGE . LPAs also act on the conceptus 2α 2 nancy . Furthermore, intramuscular estrogen injec- trophectoderm to activate the extracellular signal-regulated kinases tion into cyclic pigs increases LE expression of STAT1, 1/2 (ERK1/2) and p90 ribosomal S6 kinase (P90RSK) signaling and an intrauterine infusion of conceptus secretory pro- pathway and the p38 mitogen-activated protein kinase (MAPK) signaling pathway, which induces the expression of urokinase-type teins induces stromal expression of STAT1 , indicat- plasminogen activator (PLAU) and PTGS2 ing that conceptus estrogen and IFNs regulate cell type- specific STAT1 expression in the endometrium during (PTGS1), PTGS2, and PG synthases [144, 145]. Aldo- early pregnancy in pigs. IFN-regulatory factor 2 (IRF2), keto reductase 1B1 (AKR1B1) is the major PGF synthase known as a potential transcriptional repressor of ISGs responsible for PGF synthesis from PGH2 in bovine that works by competitively inhibiting IRF1 binding to 2α and human uterine endometria [146–148]. Our study the promoters of IFN-stimulated responsive elements of has also shown that AKR1B1 is responsible for producing ISGs , is expressed in endometrial LE cells, with PGF in the porcine endometrium . Interestingly, the greatest abundance seen during early pregnancy 2α AKR1B1 expression dramatically increases in LE cells of . Endometrial LE expression of IRF2 is increased by the endometrium on d 12 of pregnancy in pigs, coinciding estrogen, suggesting that IRF2 could suppress the ex- with conceptus estrogen production . Treatment of pression of ISGs in endometrial LE cells in pigs . In endometrial explants with estrogen and estrogen injection addition to regulating the expression of intracellular sig- into cyclic pigs up-regulate endometrial expression of naling molecules that mediate IFN actions, estrogen also AKR1B1 [10, 149], indicating that AKR1B1 is induced by affects the expression of receptors for IFNs in the endo- conceptus estrogen and responsible for increased endo- metria of pigs. Type I IFNs (including IFND) and type II metrial production of PGF . IFN (IFNG) bind to their heterodimeric type I IFN 2α Ka et al. Journal of Animal Science and Biotechnology (2018) 9:44 Page 10 of 17 receptors, IFNAR1 and IFNAR2, and type II IFN recep- abundance on d 12 of pregnancy, whereas IL1RN is tors, IFNGR1 and IFNGR2, respectively, to transduce expressed at low abundance during early pregnancy in signals into the cell [153, 155, 156]. In the porcine endo- pigs [136, 162]. Endometrial IL1R1 and IL1RAP expres- metrium, IFNAR1 and IFNAR2 are expressed primarily sion is primarily localized in endometrial LE and GE in LE cells, with the greatest abundance seen on d 12 of cells . The great abundance of IL1B, IL1R1, and pregnancy. The expression of IFNAR2, but not IFNAR1, IL1RAP and low abundance of IL1RN at the maternal– is increased by estrogen in endometrial explant cultures conceptus interface during the implantation period sug- . IFNGR1 and IFNGR2 are also expressed in the por- gest that endometrial IL1R1 and IL1RAP expression is cine endometrium (endometrial IFNGR2 expression is regulated by factors of conceptus origin, such as estro- greatest on d 12 of pregnancy), and endometrial expres- gen and IL1B, and that IL1B secreted by the conceptus sion of IFNGR2, but not IFNGR1, is increased by estro- plays a critical role in implantation by binding to IL1R1 gen in endometrial explant tissues (Choi and Ka, and IL1RAP on the uterine endometrium. Indeed, the unpublished data). These data suggest that estrogen of results from endometrial explant cultures show that conceptus origin induces endometrial expression of IFN IL1B increases the expression of IL1R1 and IL1RAP in receptors to prime the endometrium to respond to IFNs the endometrium of pigs. In addition, estradiol increases produced by the conceptus during the following few the expression of IL1RAP in endometrial tissue, indicat- days of estrogen secretion, affecting endometrial func- ing that IL1B and estrogen cooperate in the activation of tion for the establishment of pregnancy. the endometrial IL1B signaling system by activating endometrial IL1RAP expression during early pregnancy Conceptus-derived IL1B and its role in in pigs . endometrial function Conceptus IL1B IL1B, a well-known pro-inflammatory cytokine, has been PG synthesis shown to play important roles in the implantation The involvement of IL1B in PG production in the endo- process, mediating conceptus-endometrial interactions metrium has been shown in several species, including in several mammalian species, including humans, non- primates, pigs, and ruminants [4, 10, 141, 163–166]. In human primates, mice, and pigs [3, 157–159]. IL1B pro- baboons, IL1B induces the expression of endometrial duction by elongating porcine conceptuses between d 11 PTGS2 and IGFBP1 in decidualizing stromal cells to me- and d 12 of pregnancy has been known since the first re- diate trophoblast invasion and decidualization [163, 164]. port of Tuo and coworkers . Recently, Mathew and In the porcine endometrium, the expression of PG syn- colleagues have further shown that the IL1B gene thetic enzymes is also induced by IL1B [4, 10, 166]. Treat- expressed by porcine conceptuses, IL1B2, is different ing porcine endometrial explant tissue with IL1B or IL1B2 from the classic IL1B gene . The IL1 signaling system increases the expression of PTGS1, PTGS2,and AKR1B1 consists of two ligands (IL1A and IL1B), two receptors [4, 10] and the production of PGE , suggesting that (IL1R1 and IL1R2), an IL1 receptor accessory protein in addition to conceptus estrogen, IL1B is responsible for (IL1RAP), and an IL1 receptor antagonist (IL1RN) . the increased endometrial production of PGs in pigs. Re- IL1R1 is a signaling receptor, whereas IL1R2 is a decoy cently, it has been indicated that IL1B2-null porcine em- receptor that does not transduce a signal. A complex bryos develop normally to the blastocyst stage and form a composed of IL1B, IL1R1, and IL1RAP is required to normal spherical shape but fail to rapidly elongate or sur- initiate IL1B cell signaling. The porcine uterine endo- vive in utero, with reduced production of estrogen and metrium expresses IL1B, IL1R1, IL1RAP, and IL1RN dur- PGs at the maternal-conceptus interface . IL1B in- ing the estrous cycle and pregnancy [136, 162]. It has creases the expression of IL1B receptors (IL1R1 and been shown that in pigs, treatment of endometrial tissues IL1RAP)and CYP19A1 [4, 10, 166, 167], which indicates with recombinant IL1B2 proteins activates the nuclear that the actions of IL1B are critical for the conceptus- factor-kappa B (NFKB) signaling pathway in endometrial derived production of PGs and estrogen in pigs. In sheep, epithelial cells , and IL1B induces the ERK1/2 and p38 blocking PG synthesis in the conceptus and endometrium MAPK signaling pathways in the pUE endometrial epithe- results in the inhibition of conceptus elongation from the lial cell line , indicating that IL1B might activate a ovoidal or tubular form to the filamentous form during wide variety of genes in endometrial epithelial cells during early pregnancy, which indicates that PGs are essential for the establishment of pregnancy. conceptus elongation . However, it is likely that there is no direct effect of PGs on conceptus elongation in pigs, Regulation of IL1B signaling system because inhibition of PG synthesis between d 11 to d 12 The IL1B receptor subtypes, IL1R1 and IL1RAP, are of pregnancy does not block rapid elongation of concep- expressed in the endometrium with the greatest tuses from spherical to filamentous forms . Ka et al. Journal of Animal Science and Biotechnology (2018) 9:44 Page 11 of 17 PG transport movement in the uterine endometrium as related to the PGs can cross the cell membrane by simple diffusion at endocrine versus exocrine secretion of PGF .Nonethe- 2α very low amounts but require a facilitated transporter for less, the detailed mechanisms of ABCC4 and SLCO2A1 efficient influx and efflux . The best-characterized action at the cellular and molecular levels still need fur- PG transporters are the ATP-binding cassette sub-family ther study. C member 4 (ABCC4; also known as multidrug resistance-associated protein 4) [170, 171] and solute car- Salivary lipocalin 1 expression rier organic anion transporter family member 2A1 Lipocalins are a large group of small extracellular pro- (SLCO2A1; also known as PG transporter). ABCC4 is a teins that act as transporters of hydrophobic compounds transmembrane efflux transporter that can pump its sub- in aqueous biological fluids . The uterine endomet- strates across membranes against a diffusion gradient rium is known to produce various types of lipocalins, in- , and SLCO2A1 is responsible for PG influx rather cluding retinol binding protein in pigs and ruminants than efflux . The expression of ABCC4 and [184, 185], uterocalin in mares , and lipocalin 2 in SLCO2A1 in the endometrium has been shown in several mice . Salivary lipocalin (SAL1) is a member of the species. ABCC4 is expressed in the bovine endometrium lipocalin family originally identified as a boar-specific during the estrous cycle and mediates PGF and PGE se- sex pheromone-binding protein [188, 189]; it is also a 2α 2 cretion from endometrial cells , and SLCO2A1 is component of uterine secretions . SAL1 is expressed in the uterine endometrium in humans, rumi- expressed in endometrial GE cells at the greatest abun- nants, and mice [174–177]. In pigs, endometrial ABCC4 dance on d 12 of pregnancy, and endometrial SAL1 pro- and SLCO2A1 expression is biphasic during pregnancy, tein is secreted into the uterine lumen. SAL1 expression with the greatest abundance on d 12 and d 90 of preg- is increased by IL1B treatment in endometrial explants, nancy. IL1B treatment of endometrial explants from d 12 indicating that IL1B of conceptus origin induces SAL1 of the estrous cycle increases ABCC4 and SLCO2A1 ex- expression in the endometrium on d 12 of pregnancy pression . In addition, other possible PG transporters, . In addition, the abundance of SAL1 mRNA sig- ABCC1, ABCC9, SLCO4C1,and SLCO5A1, are expressed nificantly increases in an endometrium with embryos in the porcine endometrium during pregnancy, with the cloned by somatic cell nuclear transfer compared with highest expression of SLCO5A1 on d 12 of pregnancy. an endometrium with normal embryos on d 30 of preg- The expression of SLCO4C1 and SLCO5A1 is increased by nancy . These data suggest that proper expression of IL1B in endometrial tissues in pigs . These data indi- SAL1 is required for the establishment of pregnancy in cate that IL1B derived from the conceptus is involved not pigs. In porcine conceptus tissues on d 12 and d 15 of only in PG synthesis but also in PG transport in the endo- pregnancy, SAL1 mRNA is not detectable, but SAL1 metrium during the implantation period in pigs. proteins are localized in conceptus trophectoderm cells ABCC4 and SLCO2A1 are localized at either the ap- , indicating that SAL1 produced in the endo- ical or basolateral membrane, depending on the cell type metrium using IL1B of conceptus origin transports lipid [174, 179–181]. Apical localization of ABCC4 in the renal ligand(s) to the implanting conceptus. Although the proximal tubule epithelium results in urate exit from the identity of the ligand(s) and role of SAL1 at the mater- cell into the lumen , and SLCO2A1 expressed in the nal–fetal interface during the implantation period are apical membrane of polarized kidney cells is responsible not fully understood, the data published so far suggest for apical uptake of PGE . Subcellular localization of that SAL1 is a newly identified transport protein that those transport proteins seems to be important because it could play a critical role in the establishment of preg- could determine the direction of PG transport. In the por- nancy in pigs. cine endometrium, the expression of ABCC4 is localized mainly in endometrial LE and GE cells, and the expression Regulation of IFN signaling molecules of SLCO2A1 is localized primarily in endometrial LE and It has been suggested that IL1B plays an important role vascular endothelial cells . The pattern of expression in the implantation process by regulating the immune and cellular localization of ABCC4 and SLCO2A1 and response at the maternal–fetal interface , but the their mode of action suggest that ABCC4 and SLCO2A1 detailed function of IL1B in the regulation of maternal regulate uterine luminal and utero-ovarian concentrations immune response is not well understood. In humans, of PGE and PGF , resulting in high concentrations of IL1 increases production of granulocyte-macrophage 2 2α uterine luminal PGE and PGF and utero-ovarian PGE colony-stimulating factor in uNK cells, which increase 2 2α 2 at the time of conceptus elongation and the secretion of in the endometrium during the mid-secretory phase IL1B and estrogens for pregnancy recognition signaling and contribute a major cellular component of the de- and implantation. Thus, the location of those PG trans- cidua during pregnancy . Geisert and coworkers porters could be critical for regulating the direction of PG have shown that IL1B activates the NFKB signaling Ka et al. Journal of Animal Science and Biotechnology (2018) 9:44 Page 12 of 17 pathway in the endometrium [3, 4] and might be in- endometrial responsiveness during early pregnancy volved in activating a variety of cytokines that regu- in pigs (Fig. 3). Data from many researchers and our late the maternal immune response in pigs. As laboratories indicate that estrogen and IL1B derived previously stated, the porcine endometrium expresses from elongating porcine conceptuses are involved in the IFND receptors, IFNAR1 and IFNAR2,inthe cell adhesion and the production of various histo- greatest abundance on d 12 of pregnancy, and IL1B trophs that are essential for the establishment of increases the expression of IFNAR1 and IFNAR2 in pregnancy. In particular, estrogen and IL1B cooper- endometrial explant tissues obtained from the uterus ate in the endometrial expression of IFN signaling on d 12 of the estrous cycle , indicating that in molecules and prime the endometrium to increase addition to estrogen, IL1B is involved in regulating its responsiveness to the actions of IFNG and IFND, type I IFN receptor expression in the porcine endo- which are secreted by the conceptus following its metrium. IL1B also increases the expression of STAT1 production of estrogen and IL1B during early preg- in endometrial tissues (Choi and Ka, unpublished nancy. Although we have not discussed the role of data). These data suggest that one of the mechanisms conceptus-derived IFNs in this review, those critical by which IL1B regulates the maternal immune re- immune regulators change the maternal endometrial sponse in pigs could be the activation of the IFN sig- immune environment to protect the mother and in- naling pathway. crease tolerance to the semi-allograft conceptus. However, the roles of estrogen and IL1B at the ma- Conclusions ternal–conceptus interface are far from completely Establishing a pregnancy requires well-coordinated understood and require further analysis. Also, the interactions between the conceptus and the maternal mechanisms by which IFN activity affects the mater- uterine endometrium involving the tightly regulated nal immune response to achieve immune tolerance expression of genes and the production of secretory to an implanting conceptus for the maintenance of molecules from the conceptus and the endometrium. pregnancy need further study in pigs. Studies of the Inappropriate interactions result in the failure of implantation process and the molecules involved normal embryo development and lead to embryonic provide valuable opportunities to understand the mortality. This review has focused on the events that fundamental mechanisms that underlie the establish- occur at the maternal–conceptus interface and the ment of pregnancy in pigs, a species that forms a roles of conceptus-derived estrogen and IL1B in true epitheliochorial type of placenta. 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 Ka et al. Journal of Animal Science and Biotechnology (2018) 9:44 Page 13 of 17 Abbreviations 4. Mathew DJ, Newsom EM, Guyton JM, Tuggle CK, Geisert RD, Lucy MC. ABCC4: ATP-binding cassette sub-family C member 4;; AKR1B1: Aldo-keto Activation of the transcription factor nuclear factor-kappa B in uterine reductase 1B1; CL: Corpus luteum; CYP17A1: 17α-hydroxylase; luminal epithelial cells by interleukin 1 Beta 2: a novel interleukin 1 CYP19A1: Aromatase; ECM: Extracellular matrix; EGF: Epidermal growth factor; expressed by the elongating pig conceptus. Biol Reprod. 2015;92(4):107. ENPP2: Ectonucleotide pyrophosphatase/phosphodiesterase 2; ERK1/ 5. Jaeger LA, Johnson GA, Ka H, Garlow JG, Burghardt RC, Spencer TE, et al. 2: Extracellular signal–regulated kinases 1/2;; ESR1: Estrogen receptor-α; Functional analysis of autocrine and paracrine signalling at the uterine- FGF: Fibroblast growth factor; FGFR: Eibroblast growth factor receptor; conceptus interface in pigs. Reprod Suppl. 2001;58:191–207. FGFR2IIIb: Fibroblast growth factor receptor 2IIIb; GE: Glandular epithelial; 6. Croy BA, Wessels JM, Linton NF, van den Heuvel M, Edwards AK, Cellular TC. IFND: Interferon-δ; IFNG: Interferon-γ; IGF1: Insulin-like growth factor-1; molecular events in early and mid gestation porcine implantation sites: a IGFBP2: Insulin-like growth factor -binding protein 2; IL1B: Interleukin-1β; review. Soc Reprod Fertil Suppl. 2009;66:233–44. IL1R1: Interleukin-1 receptor 1; IL1RAP: Interleukin-1 receptor accessory 7. Bazer FW. Pregnancy recognition signaling mechanisms in ruminants and protein; IL1RN: Interleukin-1 receptor antagonist; IL6: Interleukin 6; pigs. J Anim Sci Biotechnol. 2013;4(1):23. IRF: Interferon-regulatory factor; LAP: Latency-associated peptide; LE: Luminal 8. Bazer FW, Thatcher WW. Theory of maternal recognition of pregnancy in epithelial; LPA: Lysophosphatidic acid; MAPK: Mitogen-activated protein swine based on estrogen controlled endocrine versus exocrine secretion of kinase; MHC: Major histocompatibility complex; MUC1: Mucin 1; prostaglandin F2alpha by the uterine endometrium. Prostaglandins. 1977; NFKB: Nuclear factor-kappa B; PAQR: Progestin and adipoQ receptor; 14(2):397–400. PGE : Prostaglandin E; PGF : Prostaglandin F ; PGR: Progesterone receptor; 2 2α 2α 9. Waclawik A, Kaczmarek MM, Blitek A, Kaczynski P, Ziecik AJ. Embryo- PGRMC: Progesterone membrane component; PLAU: Urokinase-type maternal dialogue during pregnancy establishment and implantation in the plasminogen activator; PTGS2: Prostaglandin -endoperoxide synthase 2; pig. Mol Reprod Dev. 2017;84(9):842–55. pTr: Porcine trophectoderm cells; pUE: Porcine uterine endometrial epithelial 10. Seo H, Choi Y, Shim J, Yoo I, Ka H. Comprehensive analysis of prostaglandin cells; RGD: Arg-Gly-Asp; S100G: S100 calcium-binding protein G; metabolic enzyme expression during pregnancy and the characterization of SAL1: Salivary lipocalin 1; SLCO2A1: Solute carrier organic anion transporter AKR1B1 as a prostaglandin F synthase at the maternal-conceptus interface family member 2A1; SPP1: Secreted phosphoprotein 1; STC1: Stanniocalcin 1; in pigs. Biol Reprod. 2014;90(5):99. TGF: Transforming growth factor beta; TRPV6: Transient receptor potential 11. Jang H, Choi Y, Yoo I, Han J, Kim M, Ka H. Characterization of interferon cation channel subfamily V member 6 alpha and beta receptor IFNAR1 and IFNAR2 expression and regulation in the uterine endometrium during the estrous cycle and pregnancy in pigs. Acknowledgments Theriogenology. 2017;88:166–73. The authors thank all the members of the Animal Biotechnology Laboratory, 12. Seo H, Choi Y, Shim J, Choi Y, Ka H. Regulatory mechanism for expression of Yonsei University, for their support and assistance throughout the projects. IL1B receptors in the uterine endometrium and effects of IL1B on prostaglandin synthetic enzymes during the implantation period in pigs. Biol Reprod. 2012;87(2):31. Funding 13. Seo H, Choi Y, Shim J, Yoo I, Ka H. Prostaglandin transporters ABCC4 and Support for the work from the authors’ laboratory described in this review SLCO2A1 in the uterine endometrium and conceptus during pregnancy in paper has been provided by the BioGreen 21 Program (200506030501; pigs. Biol Reprod. 2014;90(5):100. 20070301034040; 20080401034003; PJ007997; PJ009610; PJ01110301; 14. La Bonnardiere C, Martinat-Botte F, Terqui M, Lefevre F, Zouari K, Martal J, PJ01119103), the Rural Development Administration, and a National Research et al. 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Implantation mechanisms: This is a review paper; however, all results reported based on research by the insights from the sheep. Reproduction. 2004;128(6):657–68. authors was approved by the Institutional Animal Care and Use Committee 18. Lefevre F, Guillomot M, D'Andrea S, Battegay S, La Bonnardiere C. of Yonsei University. Interferon-delta: the first member of a novel type I interferon family. Biochimie. 1998;80(8-9):779–88. Competing interests 19. Joyce MM, Burghardt JR, Burghardt RC, Hooper RN, Jaeger LA, Spencer TE, The authors declare that they have no competing interests. et al. Pig conceptuses increase uterine interferon-regulatory factor 1 (IRF1), but restrict expression to stroma through estrogen-induced IRF2 in luminal Author details epithelium. Biol Reprod. 2007;77(2):292–302. Department of Biological Science and Technology, Yonsei University, Wonju 20. Joyce MM, Burghardt RC, Geisert RD, Burghardt JR, Hooper RN, Ross JW, 26493, Republic of Korea. 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Published: Jun 6, 2018