Reduced platelet aggregation in women after intercourse: a possible role for the cyclooxygenase pathway. Persistent rise in intracellular cAMP level is required to maintain the decidualized phenotype [63] in which cAMP withdrawal will cause the decidualized stromal cells to reacquire an undifferentiated phenotype [64]. Nan Fang Yi Ke Da Xue Xue Bao (2016) 36(7):936–40. doi: 10.1093/humupd/dmv055, 124. Turcotte C, Zarini S, Jean S, Martin C, Murphy RC, Marsolais D, et al. Fujisaki S, Kawano K, Haruyama Y, Mori N. Synergistic effect of progesterone on prostaglandin E modulation of the mitogenic response of human peripheral lymphocytes. Sojka DK, Yang L, Yokoyama WM. Progesterone is required for the normal embryo transport along the oviduct [132, 133]. doi: 10.1016/j.rbmo.2010.04.014, 39. Seo MJ, Oh DK. Essential elements of this information, consistent with the assumption that prostaglandins play an important role in implantation, appear to be: (i) the burst of endometrial prostaglandin production, following the blastocyst signal(s) or an artificial stimulus; (ii) the main localization of this production at the luminal epithelium and release towards the stroma; and (iii) the presence at the stromal level of ⦠Front Immunol (2014) 5:196. doi: 10.3389/fimmu.2014.00196, 45. Achache H, Revel A. Endometrial receptivity markers, the journey to successful embryo implantation. Up-regulation of EP 2 and EP 3 receptors in human tolerogenic dendritic cells boosts the immunosuppressive activity of PGE 2. Scarinci E, Tropea A, Notaristefano G, Arena V, Alesiani O, Fabozzi SM, et al. Bry K, Hallman M. Prostaglandins, inflammation, and preterm labor. doi: 10.1006/smim.2000.0320, 155. Endothelial cells have innate and immune tolerogenic function (134). Pregnancy estrogen drives the changes of T-lymphocyte subsets and cytokines and prolongs the survival of H-Y skin graft in murine model. Placenta (2008) 29(9):826–32. Among the most highly studied cells and molecules are tolerogenic dendritic cells (tol-DCs), M1 and M2 macrophages, Decidual NK cells (dNK) (CD56brightCD16−), Decidual stromal cells (DSCs), Endometrial stromal cells, Tregs (CD4+ CD25+ FOXP3+) and Decidual CD8+ EM cells (CD45RA− CCR7−), progesterone, oestrogen, Leukaemia inhibitory factor (LIF), Indoleamine-2,3-dioxygenase (IDO), and melatonin. While most information was obtained from animal studies especially in rodents, more researches need to be performed in humans in order to further explore the mechanisms underlying the diverse PGs action on multiple processes of implantation. Lu CY, Changelian PS, Unanue ER. doi: 10.1038/cddis.2014.335, 59. In PE this increases the release of FMS-like tyrosine kinase-1 (sFlt-1) and blocks free VEGF to protect the fetus from toxicity (136). Induction of prostaglandin E2 production by leukemia inhibitory factor promotes migration of first trimester extravillous trophoblast cell line, HTR-8/SVneo. Implantation is arguably the most crucial stage in the establishment of pregnancy. Joshi PC, Zhou X, Cuchens M, Jones Q. Prostaglandin E2 suppressed IL-15-mediated human NK cell function through down-regulation of common gamma-chain. Prostaglandins (PGs), derivatives of arachidonic acid, play an indispensable role in embryo implantation. Progesterone [112, 113], 17β-estradiol [114], urokinase-plasminogen activator [115], leukaemia inhibitory factor (LIF) [116], tumour necrosis factor (TNF) and interferon-γ [117], transforming growth factor beta (TGFβ), interleukin-1 and interleukin-6 (IL-1, IL-6) [118], lipopolysaccharides [119], epidermal growth factor (EGF) [120], insulin-like growth factor (IGF), and insulin-like growth factor binding protein-1 (IGFBP-1) [121] as well as trophoblast factors including hCG [122] have been reported to affect the expression and activities of MMPs and TIMPs. A large number of cells and molecules are related to signaling networks, which regulate tolerance to implantation and maintenance of the embryo and fetus. doi: 10.1089/scd.2013.0079, 25. doi: 10.1016/S0092-8674(00)80402-X, 148. Francis VA, Abera AB, Matjila M, Millar RP, Katz AA. PGE(2) suppression of innate immunity during mucosal bacterial infection. Gonadotropin-releasing hormone type II (GnRH-II) agonist regulates the motility of human decidual endometrial stromal cells: possible effect on embryo implantation and pregnancy. PROSTAGLANDINS 79 Eicosanoids and implantation Animal studies In rodents, the site of implantation may be characterized before the embryo implants and appears as an area of increased vascular permeability, demon- strated by the extravasation of macromolecular dyes ⦠Table 2 Principal soluble molecules acting in implantation (apposition/adhesion/invasion) to maintain fetal-maternal tolerance. doi: 10.4049/jimmunol.1602085, 185. doi: 10.1111/j.1600-0897.2011.01049.x, 20. PGE2 is secreted by the embryo, from the 2-cell embryo to the blastocyst stage. Also, DSCs inhibit dendritic cells through prostaglandin E2 (PGE2) and Indoleamine 2,3-dioxygenase (IDO), this inhibition favors the maintenance of the pregnancy (18). doi: 10.1093/jb/mvu081, 6. Interleukin-11 expression: its significance in eutopic and ectopic human implantation. Implantation occurs as a micro-trauma as the outer layer of the embryo burrows into the endometrium (1). Fertility Steril (1988) 49(2):322–7. J Reprod Fertility (1985) 73(1):139–46. Marie C, Pitton C, Fitting C, Cavaillon JM. doi: 10.1111/rda.12383, 116. doi: 10.1093/humupd/dmu009, 49. We have demonstrated previously that cyclo-oxygenase-2 (COX2), the rate- limiting enzyme in the biosynthesis of prostaglandins (PGs), is essential for blastocyst implantation and decidualization. VEGF together with angiopoietin (Ang)-1 and Ang-2 direct angiogenesis during decidualization. All are part of the complex intercommunication between the foetus and the mother. The transition into a receptive uterus includes cellular changes in the endometrium and the modulated expression of different cytokines, growth factors, transcription factors, and prostaglandins. Stavrou EX, Fang C, Bane KL, Long AT, Naudin C, Kucukal E, et al. Delayed-implantation mice were used to test for local implantation induction effects of prostaglandins E2 and F2a. Bansal AS, Bora SA, Saso S, Smith JR, Johnson MR, Thum MY. Effects of prostaglandin F2 alpha-analogue administration on luteal function, implantation of embryos and maintenance of pregnancy in bitches. Maric J, Ravindran A, Mazzurana L, Björklund ÅK, Van Acker A, Rao A, et al. An event of early pregnancy,”, H. Ni, T. Sun, X.-H. Ma, and Z.-M. Yang, “Expression and regulation of cytosolic prostaglandin E synthase in mouse uterus during the peri-implantation period,”, S. Hara, D. Kamei, Y. Sasaki, A. Tanemoto, Y. Nakatani, and M. Murakami, “Prostaglandin E synthases: understanding their pathophysiological roles through mouse genetic models,”, J. Cong, H.-L. Diao, Y.-C. Zhao, H. Ni, Y.-Q. HLA-G and its role in implantation (review). Drugs (2017) 77(17):1819–31. J Perinatol (1989) 9(1):60–5. In this work, many of those cells and molecules are analyzed. Immunol Today (1982) 3(6):153–4. Lysophosphatidic acid (LPA), a bioactive lipid derivative, was reported to enhance PGE2 synthesis and COX-2 expression in the rat uterus [28]. Preimplantation mouse embryos also express PPAR-δ, which is essential for enhancing the PGI2 effect on blastocyst hatching where impaired blastocyst formation and hatching have been reported in the PPAR-δ deficient embryos [153]. Sales, H. O. D. Critchley, and H. N. Jabbour, “Prostacyclin receptor up-regulates the expression of angiogenic genes in human endometrium via cross talk with epidermal growth factor receptor and the extracellular signaling receptor kinase 1/2 pathway,”, B. Gellersen, I. This detached multi-celled structure is called a zygote. Also, the mechanism of control over the rate of gene transcription or transcriptional regulation is altered in genes involved in chronic endometritis and the inflammatory response (IL-11, CCL4), growth factors (IGFBP1), and apoptotic proteins (BCL2, BAX, CASP8) in infertile patients (198). Received: 24 April 2020; Accepted: 19 October 2020;Published: 19 November 2020. Atallah A, Lecarpentier E, Goffinet F, Doret-Dion M, Gaucherand P, Tsatsaris V. Aspirin for Prevention of Preeclampsia. A. Sullivan, and I. M. Bird, “Endothelial vasodilator production by uterine and systemic arteries. Components in seminal plasma regulating sperm transport and elimination. Biol Reproduct (2008) 79(1):142–53. Platelet P-selectin is crucial for neutrophil recruitment (167). Am J Reprod Immunol (2019) 81(6):e13110. Sex steroids, cytokines, PGs, and growth factors have been reported to affect endometrial ECM composition in early pregnancy [106]. Berbets A, Koval H, Barbe A, Albota O, Yuzko O. Melatonin decreases and cytokines increase in women with placental insufficiency. Oettel A, Lorenz M, Stangl V, Costa SD, Zenclussen AC, Schumacher A. J Tissue Eng Regener Med (2017) 11(10):2895–911. Co-stimulation by LIF and IL-1β induced higher amount of PGE2 production and further migration of these cells [157]. Cell Immunol (1989) 120(1):61–74. Biomolecules (2020) 10(6):953. doi: 10.3390/biom10060953, 137. for successful implantation to take place: a receptive endometrium, a normal and functional embryo at the blastocyst developmental stage, and a synchronized dialogue between maternal and embry-onic tissues. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Gil-Villa AM, Norling LV, Serhan CN, Cordero D, Rojas M, Cadavid A. Aspirin triggered-lipoxin A4 reduces the adhesion of human polymorphonuclear neutrophils to endothelial cells initiated by preeclamptic plasma. Mol Hum Reproduct (2002) 8(9):841–8. doi: 10.1007/s10815-007-9148-3, 94. As for other, to the host genetically different, transplants, the possibility of a graft-versus-host reaction might also be involved in the implantation process. Haimovici F, Anderson DJ. Mixed messages: modulation of inflammation and immune responses by prostaglandins and tromboxanes. The accumulated evidence indicates that when sexual intercourse occurs and seminal fluid is deposited in the female reproductive tract, the prostaglandins in the seminal fluid, i.e., PGE2, PGE1, PGE3, and PGF2 (109), initiate a signaling cascade toward the woman’s innate immune cells. Therefore, DC does not eliminate the cellular debris which could migrate to the peritoneal cavity and grow in ectopic sites, developing as endometriosis. Hum Reprod (Oxford England) (2007) 22(7):1801–9. Clin J Am Soc Nephrol: CJASN (2016) 11(6):1102–13. A possible influence on implantation and female fertility might be via a bioactive lysophospholipid called lysophosphatidic acid (LPA). 2014, Article ID 968141, 11 pages, 2014. https://doi.org/10.1155/2014/968141, 1Department of Physiology, Faculty of Medicine, University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia. The extracellular matrix (ECM) is composed of collagens, noncollagenous multiadhesive glycoproteins, elastin, hyaluronan, proteoglycans, and glycosaminoglycans [103]. To maintain fetal-maternal tolerance in the process of implantation (apposition/adhesion/invasion), a whole network of cells and molecules regulate different factors and responses according to the stage of pregnancy. Crosstalk between decidual NK and CD14+ myelomonocytic cells results in induction of Tregs and immunosuppression. COX2 and PGE2 are related to the pathogenesis of endometriosis. doi: 10.1016/0167-5699(82)90103-7, 114. Gottlieb C, Svanborg K, Eneroth P, Bygdeman M. Effect of prostaglandins on human sperm function in vitro and seminal adenosine triphosphate content. Successful implantation requires a receptive endometrium, a normal and functional embryo at the blastocyst developmental stage and a synchroniz⦠Croxatto D, Vacca P, Canegallo F, Conte R, Venturini PL, Moretta L, et al. Analysis of the direct effects of prostaglandins on human sperm function. PloS One (2014) 9(2):e89006. Prostaglandins (PGs),derivatives of arachidonic acid, play an indispensable role in embryo implantation. Ortega MA, Asúnsolo Á, Álvarez-Rocha MJ, Romero B, De León-Luis J, Álvarez-Mon M, et al. Sex steroids have been reported to exert differential effect on these changes with estrogen increases the permeability but profoundly inhibits angiogenesis in vivo, while progesterone stimulates angiogenesis however has little effect on permeability [32]. C/EBPβ is also essential for the cAMP signaling [96]. Proc Natl Acad Sci U States A (2010) 107(26):11918–23. Prostaglandins (PGs), derivatives of arachidonic acid, play an indispensable role in embryo implantation. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Michimata T, Tsuda H, Sakai M, Fujimura M, Nagata K, Nakamura M, et al. Role of lipid mediators and control of lymphocyte responses in type 2 immunopathology. Reprod Biomed Online (2010) 21(3):304–11. Int J Fertility Steril (2017) 11(2):99–104. Sasanami T, Izumi S, Sakurai N, Hirata T, Mizushima S, Matsuzaki M, et al. Effects of cAMP and cGMP, autonomic agonists, and agents which affect microtubule function. J Visualized Experiments: JoVE (2017) 121):55168. doi: 10.3791/55168, 30. Samuelsson B. Bonnamy, A. Benhaim, and P. Leymarie, “Uterine luteinizing hormone/human chorionic gonadotropin-binding sites in the early pregnant rat uterus: evidence for total occupancy in the periimplantation period,”, N. Vitoratos, D. C. Papatheodorou, S. N. Kalantaridou, and G. Mastorakos, “‘Reproductive’ corticotropin-releasing hormone,”, G. R. Frank, A. K. Brar, M. I. Cedars, and S. Handwerger, “Prostaglandin E2 enhances human endometrial stromal cell differentiation,”, C. Ganeff, G. Chatel, C. Munaut, F. Frankenne, J.-M. Foidart, and R. Winkler, “The IGF system in in-vitro human decidualization,”, H. J. Chang, J. H. Lee, K. J. Hwang et al., “Transforming growth factor (TGF)-, N. Chegini, M. J. Rossi, and B. J. Masterson, “Platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and EGF and PDGF, G. M. Yee and T. G. Kennedy, “Prostaglandin E2, cAMP and cAMP-dependent protein kinase isozymes during decidualization of rat endometrial stromal cells in vitro,”, S. A. Milne, G. B. Perchick, S. C. Boddy, and H. N. Jabbour, “Expression, localization, and signaling of PGE2 and EP2/EP4 receptors in human nonpregnant endometrium across the menstrual cycle,”, E. Dimitriadis, C. Stoikos, M. Baca, W. D. Fairlie, J. E. McCoubrie, and L. A. Salamonsen, “Relaxin and prostaglandin E2 regulate interleukin 11 during human endometrial stromal cell decidualization,”, J. Kang, P. Chapdelaine, P. Y. Laberge, and M. A. Fortier, “Functional characterization of prostaglandin transporter and terminal prostaglandin synthases during decidualization of human endometrial stromal cells,”, J. 101. Due to its luteolytic action, prostaglandin F2-alpha (PGF2α) is mainly considered as an undesirable factor during early pregnancy. PGE2 was demonstrated to promote blastocyst hatching and enhance trophoblast proliferation after embryo transfer [75, 76 doi: 10.1002/bdr2.1419, 13. Hum Reprod (Oxford England) (2012) 27(12):3540–51. doi: 10.1530/JOE-13-0565, 26. doi: 10.1111/aji.13106, 28. Biol Reprod (1994) 51(6):1279–84. In women, Treg cell deficiency is linked with unexplained infertility, miscarriage, and pre-eclampsia. Int Immunopharmacol (2019) 74:105730. doi: 10.1016/j.intimp.2019.105730, 27. doi: 10.1016/0165-0378(85)90018-x, 41. Also, it inhibits the production of IFN-α in plasmacytoid dendritic cells and the production of IL-12 in myeloid dendritic cells. doi: 10.3109/00207459108999775, 194. In rodents, PGE2 and PGF2α have been reported to play important role in blastocyst spacing, implantation, and decidualization while PGI2 (prostacyclin) has been implicated in implantation and decidualization involving PPAR-δ [23]. Prostacyclin (PGI2) is the most abundant PGs produced by the mouse blastocysts. Zavazava N, Krönke M. Soluble HLA class I molecules induce apoptosis in alloreactive cytotoxic T lymphocytes. There are currently two identified PTGS isozymes: a constitutive PTGS1 (COX-1) and inducible PTGS2 (COX-2), which differ in their expression and tissue distribution [3]. Vrtačnik P, Ostanek B, Mencej-Bedrač S, Marc J. doi: 10.1016/j.anireprosci.2005.07.005, 119. doi: 10.1016/j.colsurfb.2014.09.040, 166. Meanwhile, COX-1 is expressed in the luminal and glandular epithelia while COX-2 is expressed in the luminal epithelia and perivascular cells during the implantation window period in humans [20]. PGF2 can be synthesized directly from PGH2 or indirectly via PGE2 while PGI2 could derive either directly from PGH2 or indirectly via PGD2 [8]. T lymphocytes are targets for platelet- and trophoblast-derived microvesicles during pregnancy. New target cells of the immunomodulatory effects of progesterone. Although the presence of PGs (PGE2, PGF2α, PGI2) ⦠These vesicles transport immunomodulatory proteins such as Fas ligand, TRAIL, CD274, CD276, HLA-G5, Syncytin-1, hCG, glycodelin, galectin-1 (107), which may maintain fetal-maternal tolerance, and may even be related to recurrent early miscarriage (108). Flórez-Grau G, Cabezón R, Borgman KJE, España C, Lozano JJ, Garcia-Parajo MF, et al. doi: 10.1053/plac.2002.0816. Stimulation by human chorionic gonadotropin of prostaglandin synthesis by early human placental tissue. doi: 10.1530/REP-11-0021, 87. doi: 10.1002/term.2193, 12. In early pregnancy in rats, COX-2 expression is increased between days 2 to 5 [89] suggesting that PGs are required in the process of stromal cells decidualization. doi: 10.1016/0014-2999(80)90098-9, 78. Blood (2005) 105(3):1078–84. doi: 10.1073/pnas.1001749107, 159. Human Reproduction 10 (Suppl. Mediators and molecular pathways involved in the regulation of neutrophil extracellular trap formation mediated by activated platelets. Int J Mol Sci (2018) 19(9):2802. doi: 10.3390/ijms19092802. The combination of platelets and neutrophil extracellular traps (Nets), uterine innate lymphoid cells (uILC), Treg cells, NK cells, and sex hormones have an important function in immunological tolerance. Eicosanoids correspond to 15R-epimers of lipoxins (ATL) and are potent inhibitors of leukotriene B4-mediated neutrophils (140). Immunology (2002) 107(3):281–7. Exp Ther Med (2018) 16(6):5130–6. Neutrophils are then recruited for the elimination of excess sperm through phagocytosis (177). Mediators Inflamm (1996) 5(5):334–40. TheScientificWorldJournal (2011) 11:235–41. In mice, insufficient Treg cell activity results in implantation failure, or constrains placental function and fetal growth. AIDS Res Hum Retroviruses (2019) 35(6):553–6. In mice, increased vascular permeability could be seen at day 4.5 of the oestrous cycle, as evidence from a contrast-enhanced (CE)-MRI and fluorescence microscopic studies [31]. Prostaglandin E 2 has a profound effect on embryo development, hatching, and embryo implantation (Niringiyumukiza et al., 2018). Decidual Tissue Contains Differentiated CD8+ Effector-Memory T Cells with Unique Properties. Reprod Sci (Thousand Oaks Calif) (2018) 25(4):550–8. ... preparingtheuterus for embryo implantation. Proliferation and decidualization of endometrial stromal cells during embryo-attachment stage in bonnet monkeys (Macaca radiata). ... are not recommended for use by pregnant women because of embryo implantation problems found in animal studies. doi: 10.1016/j.jaci.2018.02.006, 152. Embryo implantation is associated with an active Th1 inflammatory response while a Th2-humoral inflammation is required for pregnancy maintenance. We focus on platelets, polymorphonuclear leukocytes, and group 2 innate lymphoid cells involved in embryo tolerance in order to have a wider view of how prostaglandins participate. Semin Immunol (2016) 28(6):561–9. Changes in vascular permeability are followed by progressive increase in angiogenesis [31]. Biomed Pharmacother Biomed Parmacother (2017) 88:95–101. In mice, prostacyclin (PGI2) is the primary prostaglandin at the implantation site. Biomed Pharmacother Biomed Parmacother (2016) 80:102–8. In addition, it causes molecular and cellular changes in the endometrium. However, only a few studies on individual PGs in female reproduction have been done so far. (166) found that platelets act through P-selectin glycoprotein ligand-1 (PSGL-1), and directly affect neutrophil extracellular traps (NETosis). Treatment with exogenous progesterone increases pregnancy success through the expression of genes responsible for vascular function and PGE2 synthesis (197). Arachidonic Acid Metabolism and Kidney Inflammation. Marcus AJ, Safier LB, Broekman MJ, Ullman HL, Islam N, Sorrell TC, et al. The prostaglandins present in seminal fluid have a role in immune modulation. Through different molecules such as IL-1β, steroid hormones, insulin-like growth-factor-binding protein-1 (IGFBP-1) and prostaglandin-endoperoxide synthase-2 (PTGS-2), the decidualized cells regulate this stage with the invasion of embryos, and the formation of the placenta (110). doi: 10.14670/HH-11-948, 91. However, its content in the uterine lumen is elevated in pigs and other mammals. Remove your nail polish. COX is the key enzyme in PG biosynthesis, acting both as dioxygenase and peroxidase [2]. Reprod Biol Endocrinol (2018) 16(1):43. doi: 10.1186/s12958-018-0359-5, 112. Fast and free shipping free returns cash on delivery available on eligible purchase. PGs have been reported to participate in the increase in vascular permeability, stromal decidualization, blastocyst growth and development, leukocyte recruitment, embryo transport, trophoblast invasion, and extracellular matrix remodeling during implantation. doi: 10.1161/ATVBAHA.120.314330, 135. Szymanska M, Blitek A. Endometrial and conceptus response to exogenous progesterone treatment in early pregnant gilts following hormonally-induced estrus. According to the cytokine profile and transcription factor, ILCs are divided into two groups, cytotoxic and “helper”-ILC (17). J Reprod Immunol (2002) 57(1-2):143–50. Pregnancy and implantation What is embryo implantation? doi: 10.1111/cei.12790, 37. doi: 10.1093/molehr/gar015, 85. Herrler A, von Rango U, Beier HM, Wu HM, Huang HY, Lee CL, et al. The possible involvement of prostaglandins (PGs) in events of ovum implantation is investigated. doi: 10.1111/aji.12076, Keywords: prostaglandins, PGE2, platelets, polymorphonuclear leukocyte, group 2 innate lymphoid cells, embryo tolerance, Citation: Mayoral Andrade G, Vásquez Martínez G, Pérez-Campos Mayoral L, Hernández-Huerta MT, Zenteno E, Pérez-Campos Mayoral E, Martínez Cruz M, Martínez Cruz R, Matias-Cervantes CA, Meraz Cruz N, Romero Díaz C, Cruz-Parada E and Pérez-Campos E (2020) Molecules and Prostaglandins Related to Embryo Tolerance. Prostacyclin (PGI2), a potent vasodilator, has been reported to play important role in the increase in vascular permeability at the implantation site. Other cells assisting in the decidualization of endometrial stromal cells (ESCs) and pregnancy maintenance are decidual natural killer (dNK) cells (157) and CD14+ cells for Treg induction and immunosuppression (158). Agostinis C, Tedesco F, Bulla R. Alternative functions of the complement protein C1q at embryo implantation site. doi: 10.1111/j.1600-0897.1998.tb00345.x, 63. Vazquez J, Chavarria M, Li Y, Lopez GE, Stanic AK. During the peri-implantation period, porcine conceptuses undergo rapid transformation. 76. doi: 10.1159/000484378, 106. In embryos, gradually increasing levels of PGE2 from a 2-cell embryo to blastocyst were identified . doi: 10.1101/cshperspect.a023028, 108. Shahnazi M, Nouri M, Mohaddes G, Latifi Z, Fattahi A, Mohammadi M. Prostaglandin E Pathway in Uterine Tissue During Window of Preimplantation in Female Mice Mated With Intact and Seminal Vesicle-Excised Male. Reprod Biomed Online (2003) 6(2):244–56. The seminal fluid start an immune signaling pathways mediated by PGE2 and PGI2 in the functions of endothelial cells, platelets, neutrophils, ILC2, lymphocytes, macrophages, natural killer, dendritic cells and monocytes during oocyte fertilization and early implantation.