Skip to main content

Actions of Seminal Plasma Cytokines in Priming Female Reproductive Tract Receptivity for Embryo Implantation

  • Chapter
Immunology of Pregnancy

Abstract

Embryo implantation is critically dependent on a supportive uterine environment. Uterine receptivity is the culmination of a cellular and molecular transformation mediated locally by paracrine signals under the governance of ovarian steroid hormones, with cells and cytokines of the immune system playing integral roles in this process. Semen is now recognised as contributing to endometrial preparation for embryo implantation, through the agency of specific factors in the seminal plasma fraction of the ejaculate. Transforming growth factor-β (TGFβ) and other immunoactive moieties derived from male accessory glands interact with epithelial cells in female reproductive tissues to induce pro-inflammatory cytokine expression and initiate an inflammatory cascade. The consequences are recruitment and activation of macrophages, granulocytes and dendritic cells which have immune-regulatory and tissue remodelling roles. The cytokines elicited by seminal activation also exert embryotrophic effects and contribute to optimal preimplantation embryo development. This review summarises our current understanding of the molecular and cellular basis of interactions between seminal plasma and the female reproductive tract, and explores the potential mechanisms through which seminal plasma influences the establishment of pregnancy.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. De M, Choudhuri R, Wood GW. Determination of the number and distribution of macrophages, lymphocytes, and granulocytes in the mouse uterus from mating through implantation. J Leukocyte Biol 1991;50:252–262.

    PubMed  CAS  Google Scholar 

  2. Robertson SA, Mau VJ, Tremellen KP et al. Role of high molecular weight seminal vesicle proteins in eliciting the uterine inflammatory response to semen in mice. J Reprod Fertil 1996;107:265–277.

    Article  PubMed  CAS  Google Scholar 

  3. McMaster MT, Newton RC, Dey SK et al. Activation and distribution of inflammatory cells in the mouse uterus during the preimplantation period. J Immunol 1992;148:1699–1705.

    PubMed  CAS  Google Scholar 

  4. Robertson SA, Allanson M, Mau VJ. Molecular regulation of uterine leukocyte recruitment during early pregnancy in the mouse. Trophoblast Res 1998;11:101–120.

    CAS  Google Scholar 

  5. Lovell JW, Getty R. Fate of semen in the uterus of the sow: Histologic study of endometrium during the 27 hours after natural service. Am J Vet Res 1968;29:609–625.

    PubMed  CAS  Google Scholar 

  6. O’Leary S, Jasper MJ, Warnes GM et al. Seminal plasma regulates endometrial cytokine expression, leukocyte recruitment and embryo development in the pig. Reproduction 2004;128:237–247.

    Article  PubMed  CAS  Google Scholar 

  7. Pandya IJ, Cohen J. The leukocytic reaction of the human cervix to spermatozoa. Fertil Steril 1985;43:417–421.

    PubMed  CAS  Google Scholar 

  8. Robertson SA, Sharkey DJ, Tremellen KP et al. Semen elicits immunological changes in the human cervix. J Soc Gynecol Invest 2001;9:228A.

    Google Scholar 

  9. Sharkey DJ, Jasper MJ, Tremellen KP et al. Pro-inflammatory cytokine mRNA expression is induced within the human cervix following insemination. Biol Reprod 2004; 221. (37th Annual Meeting of the Society for the Study of Reproduction).

    Google Scholar 

  10. Tremellen KP, Robertson SA. Potential role of seminal plasma TGFbeta in the initiation of the post-coital inflammatory response in humans. J Reprod Immunol 1997;34:76.

    Article  Google Scholar 

  11. Gutsche S, von Wolff M, Strowitzki T et al. Seminal plasma induces mRNA expression of IL-1beta, IL-6 and LIF in endometrial epithelial cells in vitro. Mol Hum Reprod 2003;9:785–791.

    Article  PubMed  CAS  Google Scholar 

  12. Pang SF, Chow PH, Wong TM. The role of the seminal vesicle, coagulating glands and prostate glands on the fertility and fecundity of mice. J Reprod Fertil 1979;56:129–132.

    Article  PubMed  CAS  Google Scholar 

  13. O WS, Chen HQ, Chow PH. Effects of male accessory sex gland secretions on early embryonic development in the golden hamster. J Reprod Fertil 1988;84:341–344.

    PubMed  CAS  Google Scholar 

  14. Queen F, Dhabuwala CB, Pierrepoint CG. The effect of removal of the various accessory sex glands on the fertility of male rats. J Reprod Fertil 1981;62:423–436.

    PubMed  CAS  Google Scholar 

  15. Peitz B, Olds Clarke P. Effects of seminal vesicle removal on fertility and uterine sperm motility in the house mouse. Biol Reprod 1986;35:608–617.

    Article  PubMed  CAS  Google Scholar 

  16. Watson JG, Carroll J, Chaykin S. Reproduction in mice: The fate of spermatozoa not involved in fertilization. Gamete Res 1983;7:75–84.

    Article  Google Scholar 

  17. Bromfield JJ, Roberts CT, Robertson SA. Seminal plasma programs uterine receptivity and pregnancy outcome. Biol Reprod 2004; 94. (37th Annual Meeting of the Society for the Study of Reproduction).

    Google Scholar 

  18. Carp HJ, Serr DM, Mashiach S et al. Influence of insemination on the implantation of transferred rat blastocysts. Gynecol Obstet Invest 1984;18:194–198.

    Article  PubMed  CAS  Google Scholar 

  19. Murray FA, Grifco P, Parker CF. Increased litter size in gilts by intrauterine infusion of seminal and sperm antigens before mating. J Anim Sci 1983;56:895–900.

    PubMed  CAS  Google Scholar 

  20. Mah J, Tilton JE, Williams GL et al. The effect of repeated mating at short intervals on reproductive performance of gilts. J Anim Sci 1985;60:1052–1054.

    PubMed  CAS  Google Scholar 

  21. Bellinge BS, Copeland CM, Thomas TD et al. The influence of patient insemination on the implantation rate in an in vitro fertilization and embryo transfer program. Fertil Steril 1986;46:2523–2526.

    Google Scholar 

  22. Tremellen KP, Valbuena D, Landeras J et al. The effect of intercourse on pregnancy rates during assisted human reproduction. Hum Reprod 2000;15:2653–2658.

    Article  PubMed  CAS  Google Scholar 

  23. Coulam CB, Stern JJ. Seminal plasma treatment of recurrent spontaneous abortion. In: Dondero F, Johnson PM, eds. Serono Symposia publications from Raven Press; Reproductive Immunology. New York: Raven Press, 1993:205–206.

    Google Scholar 

  24. Klonoff-Cohen HS, Savitz DA, Celafo RC et al. An epidemiologic study of contraception and preeclampsia. JAMA 1989;262:3143–3147.

    Article  PubMed  CAS  Google Scholar 

  25. Robillard PY, Hulsey TC, Perianin J et al. Association of pregnancy-induced hypertension with duration of sexual cohabitation before conception. The Lancet 1995;344:973–975.

    Article  Google Scholar 

  26. Dekker GA, Robillard PY, Hulsey TC. Immune maladaptation in the etiology of preeclampsia: A review of corroborative epidemiologic studies. Obstet Gynecol Surv 1998;53:377–382.

    Article  PubMed  CAS  Google Scholar 

  27. Salha O, Sharma V, Dada T et al. The influence of donated gametes on the incidence of hypertensive disorders of pregnancy. Hum Reprod 1999;14:2268–2273.

    Article  PubMed  CAS  Google Scholar 

  28. Tremellen KP, Seamark RF, Robertson SA. Seminal transforming growth factor betal stimulates granulocyte-macrophage colony-stimulating factor production and inflammatory cell recruitment in the murine uterus. Biol Reprod 1998;58:1217–1225.

    Article  PubMed  CAS  Google Scholar 

  29. Robertson SA, Ingman WV, O’Leary S et al. Transforming growth factor beta-a mediator of immune deviation in seminal plasma. J Reprod Immunol 2002;57:109.

    Article  PubMed  CAS  Google Scholar 

  30. Sharkey DJ, Robertson SA. Seminal plasma TGFbeta activates pro-inflammatory cytokine synthesis in human cervical epithelial cells. Reprod Fertil Develop 2004;16(suppl):80.

    Google Scholar 

  31. Lokeshwar BL, Block NL. Isolation of a prostate carcinoma cell proliferation-inhibiting factor from human seminal plasma and its similarity to transforming growth factor beta. Cancer Res 1992;52:5821–5825.

    PubMed  CAS  Google Scholar 

  32. Nocera M, Chu TM. Characterization of latent transforming growth factor-beta from human seminal plasma. Am J Reprod Immunol 1995;33:282–291.

    PubMed  CAS  Google Scholar 

  33. Srivastava MD, Lippes J, Srivastava BI. Cytokines of the human reproductive tract. Am J Reprod Immunol 1996;36:157–166.

    PubMed  CAS  Google Scholar 

  34. Denison FC, Calder AA, Kelly RW. The action of prostaglandin E2 on the human cervix: Stimulation of interleukin 8 and inhibition of secretory leukocyte protease inhibitor. Am J Obstet Gynecol 1999;180:614–620.

    Article  PubMed  CAS  Google Scholar 

  35. Sivaramakrishnan G, Jasper MJ, O’Leary S et al. Probiotic lactobacillus in semen. Reprod Fertil Develop 2004;16(suppl):95.

    Google Scholar 

  36. Schaefer TM, Desouza K, Fahey JV et al. Toll-like receptor (TLR) expression and TLR-mediated cytokine/chemokine production by human uterine epithelial cells. Immunol 2004;112:428–436.

    Article  CAS  Google Scholar 

  37. Glynn DJ, Sharkey DJ, Robertson SA. Interferon-gamma inhibits female reproductive tract responsiveness to seminal plasma. Biol Reprod 2004; 242. (37th Annual Meeting of the Society for the Study of Reproduction).

    Google Scholar 

  38. Chu TM, Nocera MA, Flanders KC et al. Localization of seminal plasma transforming growth factor-betal on human spermatozoa: An immunocytochemical study. Fertil Steril 1996;66:327–330.

    PubMed  CAS  Google Scholar 

  39. Kunz G, Leyendecker G. Uterine peristaltic activity during the menstrual cycle: Characterization, regulation, function and dysfunction. Reprod Biomed Online 2002;4(Suppl) 3:5–9.

    PubMed  Google Scholar 

  40. Robertson SA, Roberts CT, Farr KL et al. Fertility impairment in granulocyte-macrophage colony-stimulating factor-deficient mice. Biol Reprod 1999;60:251–261.

    Article  PubMed  CAS  Google Scholar 

  41. Rozeboom KJ, Troedsson MH, Hodson HH et al. The importance of seminal plasma on the fertility of subsequent artificial inseminations in swine. J Anim Sci 2000;78:443–448.

    PubMed  CAS  Google Scholar 

  42. Troedsson MH, Loset K, Alghamdi AM et al. Interaction between equine semen and the en-dometrium: The inflammatory response to semen. Anim Reprod Sci 2001;68:273–278.

    Article  PubMed  CAS  Google Scholar 

  43. Taylor NJ. Investigation of sperm-induced cervical leucocytosis by a double mating study in rab bits. J Reprod Fertil 1982;66:157–160.

    Article  PubMed  CAS  Google Scholar 

  44. Roldan ER, Gomendio M, Vitullo AD. The evolution of eutherian spermatozoa and underlying selective forces: Female selection and sperm competition. Biol Rev Camb Philos Soc 1992;67:551–593.

    PubMed  CAS  Google Scholar 

  45. Schimenti J. Segregation distortion of mouse t haplotypes the molecular basis emerges. Trends Genet 2000;16:240–243.

    Article  PubMed  CAS  Google Scholar 

  46. Reid BL. The fate of isotope-labelled uterine spermatozoa in the mouse post coitum. Aust J Zool 1965; 13:525–531.

    Article  Google Scholar 

  47. Beer AE, Billingham RE. Host responses to intra-uterine tissue, cellular and fetal allografts. J Reprod Ferti Suppl 1974;21:59–88.

    Google Scholar 

  48. Johansson M, Bromfield JJ, Jasper MJ et al. Semen activates the female immune response during early pregnancy in mice. Immunol 2004;112:290–300.

    Article  CAS  Google Scholar 

  49. Piazzon I, Matusevich M, Deroche A et al. Early increase in graft-versus-host reactivity during pregnancy in the mouse. J Reprod Immunol 1985;8:129–137.

    Article  PubMed  CAS  Google Scholar 

  50. Kapovic M, Rukavina D. Kinetics of lymphoproliferative responses of lymphocytes harvested from the uterine draining lymph nodes during pregnancy in rats. J Reprod Immunol 1991;20:93–101.

    Article  PubMed  CAS  Google Scholar 

  51. Clark DA, McDermott MR. Active suppression of host-vs-graft reaction in pregnant mice. III. Developmental kinetics, properties, and mechanism of induction of suppressor cells during first pregnancy. J Immunol 1981;127:1267–1273.

    PubMed  CAS  Google Scholar 

  52. Aluvihare VR, Kallikourdis M, Betz AG. Regulatory T cells mediate maternal tolerance to the fetus. Nat Immunol 2004;5:266–271.

    Article  PubMed  CAS  Google Scholar 

  53. Heyborne KD, Cranfill RL, Carding SR et al. Characterization of gamma delta T lymphocytes at the maternal-fetal interface. J Immunol 1992;149:2872–2878.

    PubMed  CAS  Google Scholar 

  54. Arck PC, Ferrick DA, Steele Norwood D et al. Murine T cell determination of pregnancy out come: I. Effects of strain, α/β T cell receptor, γ/δ T cell receptor, and γ/δ T cell subsets. Am J Reprod Immunol 1997;37:492–502.

    Google Scholar 

  55. Dang Y, Beckers J, Wang CR et al. Natural killer 1.1 (+) alpha beta T cells in the periimplantation uterus. Immunol 2000;101:484–491.

    CAS  Google Scholar 

  56. Croy BA, Chantakru S, Esadeg S et al. Decidual natural killer cells: Key regulators of placental development (a review). J Reprod Immunol 2002;57:151.

    Article  PubMed  CAS  Google Scholar 

  57. Robertson SA, Mau VJ, Hudson SA et al. Cytokine-leukocyte networks and the establishment of pregnancy. Am J Reprod Immunol 1997;37(6):438–42.

    PubMed  CAS  Google Scholar 

  58. Chantakru S, Miller C, Roach LE et al. Contributions from self-renewal and trafficking to the uterine NK cell population of early pregnancy. J Immunol 2002;168:22–28.

    PubMed  CAS  Google Scholar 

  59. Dang Y, Heyborne KD. Cutting edge: Regulation of uterine NKT cells by a fetal class I molecule other than CD1. J Immunol 2001;166:3641–3644.

    PubMed  CAS  Google Scholar 

  60. Hutter H, Dohr G. HLA expression on immature and mature human germ cells. J Reprod Immunol 1998;38:101–122.

    Article  PubMed  CAS  Google Scholar 

  61. Brogi A, Presentini R, Moretti E et al. New insights into the interaction between the gpl20 and the HIV receptor in human sperm. J Reprod Immunol 1998;41:213–231.

    Article  PubMed  CAS  Google Scholar 

  62. Thaler CJ. Immunological role for seminal plasma in insemination and pregnancy. Am J Reprod Immunol 1989;21:147–150.

    PubMed  CAS  Google Scholar 

  63. Rodriguez CS, Arnaiz VA. Human cells other than spermatozoa stimulate lymphocyte cultures. Tissue Antigens 1982;19:313–314.

    Article  Google Scholar 

  64. Koelman CA, Coumans ABC, Nijman HW et al. Correlation between oral sex and a low incidence of preeclampsia: A role for soluble HLA in seminal fluid? J Reprod Immunol 2000;46:155–166.

    Article  PubMed  CAS  Google Scholar 

  65. Letterio JJ, Roberts AB. Regulation of immune responses by TGF-beta. Annu Rev Immunol 1998;16:137–161.

    Article  PubMed  CAS  Google Scholar 

  66. Weiner HL. Oral tolerance: Immune mechanisms and the generation of Th3-type TGF-beta-secreting regulatory cells. Microbes Infect 2001;3:947–954.

    Article  PubMed  CAS  Google Scholar 

  67. Lengerova A, Vojtiskova M. Prolonged survival of syngenic male skin grafts in parous C57 B1 mice. Folia Biol 1966;8:21.

    Google Scholar 

  68. Hancock RJ, Faruki S. Assessment of immune responses to H-Y antigen in naturally inseminated and sperm-injected mice using cell-mediated cytotoxicity assays. J Reprod Immunol 1986;9:187–194.

    Article  PubMed  CAS  Google Scholar 

  69. Robertson SA, Bromfield JJ, Tremellen KP. Seminal ‘priming’ for protection from preeclampsia-a unifying hypothesis. J Reprod Immunol 2003;59:253–265.

    Article  PubMed  Google Scholar 

  70. Beer AE, Billingham RE, Scott JR. Immunogenetic aspects of implantation, placentation and feto-placental growth rates. Biol Reprod 1975;126:176–189.

    Article  Google Scholar 

  71. Tofoski JG, Gill TJ-r. The production of migration inhibitory factor and reproductive capacity in allogeneic pregnancies. Am J Pathol 1977;88:333–344.

    PubMed  CAS  Google Scholar 

  72. Curry Jr TE, Osteen KG. The matrix metalloproteinase system: Changes, regulation, and impact throughout the ovarian and uterine reproductive cycle. Endocr Rev 2003;24:428–465.

    Article  PubMed  CAS  Google Scholar 

  73. Das SK, Yano S, Wang J et al. Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in the mouse uterus during the peri-implantation period. Dev Genet 1997; 21:44–54.

    Article  PubMed  CAS  Google Scholar 

  74. Feng J, Woessner Jr JF, Zhu C. Matrilysin activity in the rat uterus during the oestrous cycle and implantation. J Reprod Fertil 1998;114:347–350.

    Article  PubMed  CAS  Google Scholar 

  75. Zhao YG, Xiao AZ, Cao XM et al. Expression of matrix metalloproteinase-2,-9 and tissue inhibi tors of metalloproteinase-1,-2,-3 mRNAs in rat uterus during early pregnancy. Mol Reprod Dev 2002;62:149–158.

    Article  PubMed  CAS  Google Scholar 

  76. Chow PH, Jiang HY, Poon HK et al. Embryos sired by males without accessory sex glands induce failure of uterine support: A study of VEGF, MMP and TGF expression in the golden hamster. Anat Embryol (Berl) 2003;206:203–213.

    PubMed  CAS  Google Scholar 

  77. Bollwein H, Sowade C, Stolla R. The effect of semen extender, seminal plasma and raw semen on uterine and ovarian blood flow in mares. Theriogenology 2003;60:607–616.

    Article  PubMed  Google Scholar 

  78. Seo KH, Ko HM, Choi JH et al. Essential role for platelet-activating factor-induced NF-kappaB activation in macrophage-derived angiogenesis. Eur J Immunol 2004;34:2129–2137.

    Article  PubMed  CAS  Google Scholar 

  79. Aplin JD. Adhesion molecules in implantation. Rev Reprod 1997;2:84–93.

    Article  PubMed  CAS  Google Scholar 

  80. Kosaka K, Fujiwara H, Tatsumi K et al. Human peripheral blood mononuclear cells enhance cell-cell interaction between human endometrial epithelial cells and BeWo-cell spheroids. Hum Reprod 2003;18:19–25.

    Article  PubMed  CAS  Google Scholar 

  81. Zareie M, McKay DM, Kovarik GG et al. Monocyte/macrophages evoke epithelial dysfunction: Indirect role of tumor necrosis factor-alpha. Am J Physiol 1998;275:C932–939.

    PubMed  CAS  Google Scholar 

  82. Pampfer S, Arceci RJ, Pollard JW. Role of colony stimulating factor-1 (CSF-1) and other lympho-hematopoietic growth factors in mouse preimplantation development. Bioessays 1991;13:535–540.

    Article  PubMed  CAS  Google Scholar 

  83. Kane MT, Morgan PM, Coonan C. Peptide growth factors and preimplantation development. Hum Reprod Update 1997;3:137–157.

    Article  PubMed  CAS  Google Scholar 

  84. Robertson SA, Mayrhofer G, Seamark RF. Ovarian steroid hormones regulate granulocyte-macrophage colony-stimulating factor synthesis by uterine epithelial cells in the mouse. Biol Reprod 1996;54:183–196.

    Article  PubMed  CAS  Google Scholar 

  85. Zhao Y, Chegini N. Human fallopian tube expresses granulocyte-macrophage colony stimulating factor (GM-CSF) and GM-CSF alpha and beta receptors and contain immunoreactive GM-CSF protein. J Clin Endocrinol Metab 1994;79:662–665.

    Article  PubMed  CAS  Google Scholar 

  86. Imakawa K, Helmer SD, Nephew KP et al. A novel role for GM-CSF: Enhancement of pregnancy specific interferon production, ovine trophoblast protein-1. Endocrinol 1993;132:1869–1871.

    Article  CAS  Google Scholar 

  87. Emond V, MacLaren LA, Kimmins S et al. Expression of cyclooxygenase-2 and granulocyte-macrophage colony-stimulating factor in the endometrial epithelium of the cow is up-regulated during early pregnancy and in response to intrauterine infusions of interferon-tau. Biol Reprod 2004;70:54–64.

    Article  PubMed  CAS  Google Scholar 

  88. Robertson SA, Sjoblom C, Jasper MJ et al. Granulocyte-macrophage colony-stimulating factor pro motes glucose transport and blastomere viability in murine preimplantation embryos. Biol Reprod 2001;64:1206–1215.

    Article  PubMed  CAS  Google Scholar 

  89. Sjoblom C, Wikland M, Robertson SA. Granulocyte-macrophage colony-stimulating factor promotes human blastocyst development in vitro. Hum Reprod 1999;14:3069–3076.

    Article  PubMed  CAS  Google Scholar 

  90. Robertson SA, Mayrhofer G, Seamark RF. Uterine epithelial cells synthesize granulocyte-macrophage colony-stimulating factor and interleukin-6 in pregnant and nonpregnant mice. Biol Reprod 1992;46:1069–1079.

    Article  PubMed  CAS  Google Scholar 

  91. Piccinni MP, Beloni L, Livi C et al. Defective production of both leukemia inhibitory factor and type 2 T-helper cytokines by decidual T cells in unexplained recurrent abortions. Nat Med 1998;4:1020–1024.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Eurekah.com and Springer Science+Business Media

About this chapter

Cite this chapter

Robertson, S.A., Bromfield, J.J., Glynn, D.J., Sharkey, D.J., Jasper, M.J. (2006). Actions of Seminal Plasma Cytokines in Priming Female Reproductive Tract Receptivity for Embryo Implantation. In: Mor, G. (eds) Immunology of Pregnancy. Medical Intelligence Unit. Springer, New York, NY. https://doi.org/10.1007/0-387-34944-8_14

Download citation

Publish with us

Policies and ethics