Female Tract Cytokines and Developmental Programming in Embryos

  • Sarah A. RobertsonEmail author
  • Peck-Yin Chin
  • John E. Schjenken
  • Jeremy G. Thompson
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 843)


In the physiological situation, cytokines are pivotal mediators of communication between the maternal tract and the embryo. Compelling evidence shows that cytokines emanating from the oviduct and uterus confer a sophisticated mechanism for ‘fine-tuning’ of embryo development, influencing a range of cellular events from cell survival and metabolism, through division and differentiation, and potentially exerting long-term impact through epigenetic remodelling. The balance between survival agents, including GM-CSF, CSF1, LIF, HB-EGF and IGFII, against apoptosis-inducing factors such as TNFα, TRAIL and IFNg, influence the course of preimplantation development, causing embryos to develop normally, adapt to varying maternal environments, or in some cases to arrest and undergo demise. Maternal cytokine-mediated pathways help mediate the biological effects of embryo programming, embryo plasticity and adaptation, and maternal tract quality control. Thus maternal cytokines exert influence not only on fertility and pregnancy progression but on the developmental trajectory and health of offspring. Defining a clear understanding of the biology of cytokine networks influencing the embryo is essential to support optimal outcomes in natural and assisted conception.


Embryo Growth factors Cytokines Stress response Apoptosis 


Conflict of Interest Statement

Sarah Robertson is an inventor on patents concerning utility of GM-CSF in IVF culture medium and receives royalty income from ORIGIO A/S. Jeremy Thompson is a consultant to Cook Medical Pty. Ltd. and has patents on methods for in vitro oocyte maturation.


  1. Agerholm I, Loft A, Hald F, Lemmen JG, Munding B, Sorensen PD, Ziebe S. Culture of human oocytes with granulocyte-macrophage colony-stimulating factor has no effect on embryonic chromosomal constitution. Reprod Biomed Online. 2010;20:477–84.PubMedGoogle Scholar
  2. Arceci RJ, Pampfer S, Pollard JW. Expression of CSF-1/c-fms and SF/c-kit mRNA during preimplantation mouse development. Dev Biol. 1992;151:1–8.PubMedGoogle Scholar
  3. Auernhammer CJ, Melmed S. Leukemia-inhibitory factor-neuroimmune modulator of endocrine function. Endocr Rev. 2000;21:313–45.PubMedGoogle Scholar
  4. Baker J, Liu JP, Robertson EJ, Efstratiadis A. Role of insulin-like growth factors in embryonic and postnatal growth. Cell. 1993;75:73–82.PubMedGoogle Scholar
  5. Baker SJ, Reddy EP. Modulation of life and death by the TNF receptor superfamily. Oncogene. 1998;17:3261–70.PubMedGoogle Scholar
  6. Bazer FW, Spencer TE, Ott TL. Interferon tau: a novel pregnancy recognition signal. Am J Reprod Immunol. 1997;37:412–20.PubMedGoogle Scholar
  7. Bedaiwy MA, Falcone T, Goldberg JM, Attaran M, Sharma R, Miller K, Nelson DR, Agarwal A. Relationship between cytokines and the embryotoxicity of hydrosalpingeal fluid. J Assist Reprod Genet. 2005;22:161–5.PubMedCentralPubMedGoogle Scholar
  8. Behr B, Mooney S, Wen Y, Polan ML, Wang H. Preliminary experience with low concentration of granulocyte-macrophage colony-stimulating factor: a potential regulator in preimplantation mouse embryo development and apoptosis. J Assist Reprod Genet. 2005;22:25–32.PubMedCentralPubMedGoogle Scholar
  9. Bellinge BS, Copeland CM, Thomas TD, Mazzucchelli RE, O’Neil G, Cohen MJ. The influence of patient insemination on the implantation rate in an in vitro fertilization and embryo transfer program. Fertil Steril. 1986;46:2523–6.Google Scholar
  10. Bhatnagar P, Papaioannou VE, Biggers JD. CSF-1 and mouse preimplantation development in vitro. Development. 1995;121:1333–9.PubMedGoogle Scholar
  11. Bhatt H, Brunet LJ, Stewart CL. Uterine expression of leukemia inhibitory factor coincides with the onset of blastocyst implantation. Proc Natl Acad Sci U S A. 1991;88:11408–12.PubMedCentralPubMedGoogle Scholar
  12. Block J, Hansen PJ, Loureiro B, Bonilla L. Improving post-transfer survival of bovine embryos produced in vitro: actions of insulin-like growth factor-1, colony stimulating factor-2 and hyaluronan. Theriogenology. 2011;76:1602–9.PubMedGoogle Scholar
  13. Boehm U, Klamp T, Groot M, Howard JC. Cellular responses to interferon-γ. Annu Rev Immunol. 1997;15:749–95.PubMedGoogle Scholar
  14. Boulton TG, Cobb MH. Identification of multiple extracellular signal-regulated kinases (ERKs) with antipeptide antibodies. Cell Regul. 1991;2:357–71.PubMedCentralPubMedGoogle Scholar
  15. Brison DR, Schultz RM. Apoptosis during mouse blastocyst formation: evidence for a role for survival factors including transforming growth factor alpha. Biol Reprod. 1997;56:1088–96.PubMedGoogle Scholar
  16. Bromfield JJ, Schjenken JE, Chin PY, Care AS, Jasper MJ, Robertson SA. Maternal tract factors contribute to paternal seminal fluid impact on metabolic phenotype in offspring. Proc Natl Acad Sci U S A. 2014;111(6):2200–5.Google Scholar
  17. Bulletti C, De Ziegler D, Giacomucci E, Polli V, Rossi S, Alfieri S, Flamigni C. Vaginal drug delivery: the first uterine pass effect. Ann N Y Acad Sci. 1997;828:285–90.PubMedGoogle Scholar
  18. Byrne AT, Southgate J, Brison DR, Leese HJ. Effects of insulin-like growth factors I and II on tumour-necrosis-factor-alpha-induced apoptosis in early murine embryos. Reprod Fertil Dev. 2002a;14:79–83.PubMedGoogle Scholar
  19. Byrne AT, Southgate J, Brison DR, Leese HJ. Regulation of apoptosis in the bovine blastocyst by insulin and the insulin-like growth factor (IGF) superfamily. Mol Reprod Dev. 2002b;62:489–95.PubMedGoogle Scholar
  20. Callard RE, Gearing AJH. The cytokine facts book. London: Academic; 1994.Google Scholar
  21. Cantley LC. The Phosphoinositide 3-Kinase pathway. Science. 2002;296:1655–7.PubMedGoogle Scholar
  22. Carlsson B, Hillensjo T, Nilsson A, Tornell J, Billig H. Expression of insulin-like growth factor-I (IGF-I) in the rat fallopian tube: possible autocrine and paracrine action of fallopian tube-derived IGF-I on the fallopian tube and on the preimplantation embryo. Endocrinology. 1993;133:2031–9.PubMedGoogle Scholar
  23. Caspary T, Cleary MA, Baker CC, Guan XJ, Tilghman SM. Multiple mechanisms regulate imprinting of the mouse distal chromosome 7 gene cluster. Mol Cell Biol. 1998;18:3466–74.PubMedCentralPubMedGoogle Scholar
  24. Ceelen M, van Weissenbruch MM, Roos JC, Vermeiden JP, van Leeuwen FE, Delemarre-van de Waal HA. Body composition in children and adolescents born after in vitro fertilization or spontaneous conception. J Clin Endocrinol Metab. 2007;92:3417–23.PubMedGoogle Scholar
  25. Ceelen M, van Weissenbruch MM, Vermeiden JP, van Leeuwen FE, Delemarre-van de Waal HA. Cardiometabolic differences in children born after in vitro fertilization: follow-up study. J Clin Endocrinol Metab. 2008;93:1682–8.PubMedGoogle Scholar
  26. Chaouat G, Menu E, Clark DA, Dy M, Minkowski M, Wegmann TG. Control of fetal survival in CBA x DBA/2 mice by lymphokine therapy. J Reprod Fertil. 1990;89:447–58.PubMedGoogle Scholar
  27. Chaouat G, Ledee-Bataille N, Dubanchet S, Zourbas S, Sandra O, Martal J. TH1/TH2 paradigm in pregnancy: paradigm lost? Cytokines in pregnancy/early abortion: reexamining the TH1/TH2 paradigm. Int Arch Allergy Immunol. 2004;134:93–119.PubMedGoogle Scholar
  28. Charnock-Jones DS, Sharkey AM, Fenwick P, Smith SK. Leukaemia inhibitory factor mRNA concentration peaks in human endometrium at the time of implantation and the blastocyst contains mRNA for the receptor at this time. J Reprod Fertil. 1994;101:421–6.PubMedGoogle Scholar
  29. Chen HL, Yelavarthi KK, Hunt JS. Identification of transforming growth factor-beta 1 mRNA in virgin and pregnant rat uteri by in situ hybridization. J Reprod Immunol. 1993;25:221–33.PubMedGoogle Scholar
  30. Chen JC, Johnson BA, Erikson DW, Piltonen TT, Barragan F, Chu S, Kohgadai N, Irwin JC, Greene WC, Giudice LC, Roan NR. Seminal plasma induces global transcriptomic changes associated with cell migration, proliferation and viability in endometrial epithelial cells and stromal fibroblasts. Hum Reprod. 2014;29:1255–70.PubMedGoogle Scholar
  31. Cheung LP, Leung HY, Bongso A. Effect of supplementation of leukemia inhibitory factor and epidermal growth factor on murine embryonic development in vitro, implantation, and outcome of offspring. Fertil Steril. 2003;80(Suppl 2):727–35.PubMedGoogle Scholar
  32. Chin PY, Macpherson AM, Thompson JG, Lane M, Robertson SA. Stress response genes are suppressed in mouse preimplantation embryos by granulocyte-macrophage colony-stimulating factor (GM-CSF). Hum Reprod. 2009;24:2997–3009.PubMedGoogle Scholar
  33. Chu TM, Nocera MA, Flanders KC, Kawinski E. Localization of seminal plasma transforming growth factor-beta1 on human spermatozoa: an immunocytochemical study. Fertil Steril. 1996;66:327–30.PubMedGoogle Scholar
  34. Cocchiara R, Albeggiani G, Azzolina A, Bongiovanni A, Lampiasi N, Di Blasi F, Geraci D. Effect of substance P on uterine mast cell cytokine release during the reproductive cycle. J Neuroimmunol. 1995;60:107–15.PubMedGoogle Scholar
  35. Cohen PE, Zhu L, Pollard JW. Absence of colony stimulating factor-1 in osteopetrotic (csfmop/csfmop) mice disrupts estrous cycles and ovulation. Biol Reprod. 1997;56:110–8.PubMedGoogle Scholar
  36. Constancia M, Hemberger M, Hughes J, Dean W, Ferguson-Smith A, Fundele R, Stewart F, Kelsey G, Fowden A, Sibley C, Reik W. Placental-specific IGF-II is a major modulator of placental and fetal growth. Nature. 2002;417:945–8.PubMedGoogle Scholar
  37. Croy BA, van den Heuvel MJ, Borzychowski AM, Tayade C. Uterine natural killer cells: a specialized differentiation regulated by ovarian hormones. Immunol Rev. 2006;214:161–85.PubMedGoogle Scholar
  38. Cui XS, Lee JY, Choi SH, Kwon MS, Kim T, Kim NH. Mouse granulocyte-macrophage colony-stimulating factor enhances viability of porcine embryos in defined culture conditions. Anim Reprod Sci. 2004;84:169–77.PubMedGoogle Scholar
  39. Daiter E, Pollard JW. Colony stimulating factor-1 (CSF-1) in pregnancy. Reprod Med Rev. 1992;1:83–97.Google Scholar
  40. Dalton T, Kover K, Dey SK, Andrews GK. Analysis of the expression of growth factor, interleukin-1, and lactoferrin genes and the distribution of inflammatory leukocytes in the preimplantation mouse oviduct. Biol Reprod. 1994;51:597–606.PubMedGoogle Scholar
  41. Das SK, Wang XN, Paria BC, Damm D, Abraham JA, Klagsbrun M, Andrews GK, Dey SK. Heparin-binding EGF-like growth factor gene is induced in the mouse uterus temporally by the blastocyst solely at the site of its apposition: a possible ligand for interaction with blastocyst EGF-receptor in implantation. Development. 1994;120:1071–83.PubMedGoogle Scholar
  42. De Hertogh R, Vanderheyden I, Pampfer S, Robin D, Dufrasne E, Delcourt J. Stimulatory and inhibitory effects of glucose and insulin on rat blastocyst development in vitro. Diabetes. 1991;40:641–7.PubMedGoogle Scholar
  43. de Moraes AA, Hansen PJ. Granulocyte-macrophage colony-stimulating factor promotes development of in vitro produced bovine embryos. Biol Reprod. 1997;57:1060–5.PubMedGoogle Scholar
  44. De Rycke M, Liebaers I, Van Steirteghem A. Epigenetic risks related to assisted reproductive technologies: risk analysis and epigenetic inheritance. Hum Reprod. 2002;17:2487–94.PubMedGoogle Scholar
  45. Dhar-Mascareno M, Chen J, Zhang RH, Carcamo JM, Golde DW. Granulocyte-macrophage colony-stimulating factor signals for increased glucose transport via phosphatidylinositol 3-kinase- and hydrogen peroxide-dependent mechanisms. J Biol Chem. 2003;278:11107–14.PubMedGoogle Scholar
  46. Dhar-Mascareno M, Pedraza A, Golde DW. PI3-kinase activation by GM-CSF in endothelium is upstream of Jak/Stat pathway: role of alphaGMR. Biochem Biophys Res Commun. 2005;337:551–6.PubMedGoogle Scholar
  47. Diaz-Cueto L, Gerton GL. The influence of growth factors on the development of preimplantation mammalian embryos. Arch Med Res. 2001;32:619–26.PubMedGoogle Scholar
  48. Dimitriadis E, White CA, Jones RL, Salamonsen LA. Cytokines, chemokines and growth factors in endometrium related to implantation. Hum Reprod Update. 2005;11:613–30.PubMedGoogle Scholar
  49. Do DV, Ueda J, Messerschmidt DM, Lorthongpanich C, Zhou Y, Feng B, Guo G, Lin PJ, Hossain MZ, Zhang W, Moh A, Wu Q, et al. A genetic and developmental pathway from STAT3 to the OCT4-NANOG circuit is essential for maintenance of ICM lineages in vivo. Genes Dev. 2013;27:1378–90.PubMedCentralPubMedGoogle Scholar
  50. Doherty AS, Mann MR, Tremblay KD, Bartolomei MS, Schultz RM. Differential effects of culture on imprinted H19 expression in the preimplantation mouse embryo. Biol Reprod. 2000;62:1526–35.PubMedGoogle Scholar
  51. Dunglison GF, Barlow DH, Sargent IL. Leukaemia inhibitory factor significantly enhances the blastocyst formation rates of human embryos cultured in serum- free medium. Hum Reprod. 1996;11:191–6.PubMedGoogle Scholar
  52. Eberhard WG. Postcopulatory sexual selection: Darwin’s omission and its consequences. Proc Natl Acad Sci U S A. 2009;106(Suppl 1):10025–32.PubMedCentralPubMedGoogle Scholar
  53. Elaimi A, Gardner K, Kistnareddy K, Harper J. The effect of GM-CSF on development and aneuploidy in murine blastocysts. Hum Reprod. 2012;27:1590–5.PubMedGoogle Scholar
  54. Fabian D, Juhas S, Il’kova G, Koppel J. Dose- and time-dependent effects of TNFalpha and actinomycin D on cell death incidence and embryo growth in mouse blastocysts. Zygote. 2007;15:241–9.PubMedGoogle Scholar
  55. Fichorova RN, Anderson DJ. Differential expression of immunobiological mediators by immortalized human cervical and vaginal epithelial cells. Biol Reprod. 1999;60:508–14.PubMedGoogle Scholar
  56. Fichorova RN, Cronin AO, Lien E, Anderson DJ, Ingalls RR. Response to Neisseria gonorrhoeae by cervicovaginal epithelial cells occurs in the absence of toll-like receptor 4-mediated signaling. J Immunol. 2002;168:2424–32.PubMedGoogle Scholar
  57. Fruman DA, Meyers RE, Cantley LC. Phosphoinositide kinases. Annu Rev Biochem. 1998;67:481–507.PubMedGoogle Scholar
  58. Fry RC, Batt PA, Fairclough RJ, Parr RA. Human leukaemia inhibitory factor improves the viability of cultured ovine embryos. Biol Reprod. 1992;46:470–4.PubMedGoogle Scholar
  59. Gardner DK, Wale PL, Collins R, Lane M. Glucose consumption of single post-compaction human embryos is predictive of embryo sex and live birth outcome. Hum Reprod. 2011;26:1981–6.PubMedGoogle Scholar
  60. Gearing DP, King JA, Gough NM, Nicola NA. Expression cloning of a receptor for human granulocyte-macrophage colony-stimulating factor. Embo J. 1989;8:3667–76.PubMedCentralPubMedGoogle Scholar
  61. Giacomini G, Tabibzadeh SS, Satyaswaroop PG, Bonsi L, Vitale L, Bagnara GP, Strippoli P, Jasonni VM. Epithelial cells are the major source of biologically active granulocyte macrophage colony-stimulating factor in human endometrium. Hum Reprod. 1995;10:3259–63.PubMedGoogle Scholar
  62. Gillott C. Male accessory gland secretions: modulators of female reproductive physiology and behavior. Annu Rev Entomol. 2003;48:163–84.PubMedGoogle Scholar
  63. Glabowski W, Kurzawa R, Wiszniewska B, Baczkowski T, Marchlewicz M, Brelik P. Growth factors effects on preimplantation development of mouse embryos exposed to tumor necrosis factor alpha. Reprod Biol. 2005;5:83–99.PubMedGoogle Scholar
  64. Graf U, Casanova EA, Cinelli P. The role of the Leukemia Inhibitory Factor (LIF)—pathway in derivation and maintenance of murine pluripotent stem cells. Genes. 2011;2:280–97.PubMedCentralPubMedGoogle Scholar
  65. Guerin LR, Prins JR, Robertson SA. Regulatory T-cells and immune tolerance in pregnancy: a new target for infertility treatment? Hum Reprod Update. 2009;15:517–35.PubMedCentralPubMedGoogle Scholar
  66. Guthridge MA, Stomski FC, Thomas D, Woodcock JM, Bagley CJ, Berndt MC, Lopez AF. Mechanism of activation of the GM-CSF, IL-3, and IL-5 family of receptors. Stem Cells. 1998;16:301–13.PubMedGoogle Scholar
  67. Gutsche S, von Wolff M, Strowitzki T, Thaler CJ. Seminal plasma induces mRNA expression of IL-1beta, IL-6 and LIF in endometrial epithelial cells in vitro. Mol Hum Reprod. 2003;9:785–91.PubMedGoogle Scholar
  68. Haimovici F, Hill JA, Anderson DJ. Variables affecting toxicity of human sera in mouse embryo cultures. J In Vitro Fert Embryo Transf. 1988;5:202–6.PubMedGoogle Scholar
  69. Hamatani T, Daikoku T, Wang H, Matsumoto H, Carter MG, Ko MS, Dey SK. Global gene expression analysis identifies molecular pathways distinguishing blastocyst dormancy and activation. Proc Natl Acad Sci U S A. 2004;101:10326–31.PubMedCentralPubMedGoogle Scholar
  70. Han J, Lee JD, Bibbs L, Ulevitch RJA. MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science. 1994;265:808–11.PubMedGoogle Scholar
  71. Hannan NJ, Salamonsen LA. Role of chemokines in the endometrium and in embryo implantation. Curr Opin Obstet Gynecol. 2007;19:266–72.PubMedGoogle Scholar
  72. Hannan NJ, Paiva P, Meehan KL, Rombauts LJ, Gardner DK, Salamonsen LA. Analysis of fertility-related soluble mediators in human uterine fluid identifies VEGF as a key regulator of embryo implantation. Endocrinology. 2011;152:4948–56.PubMedGoogle Scholar
  73. Hansen M, Kurinczuk JJ, Bower C, Webb S. The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization. N Engl J Med. 2002;346:725–30.PubMedGoogle Scholar
  74. Hardy K. Apoptosis in the human embryo. Rev Reprod. 1999;4:125–34.PubMedGoogle Scholar
  75. Hardy K, Spanos S. Growth factor expression and function in the human and mouse preimplantation embryo. J Endocrinol. 2002;172:221–36.PubMedGoogle Scholar
  76. Harper J, Cristina Magli M, Lundin K, Barratt CL, Brison D. When and how should new technology be introduced into the IVF laboratory? Hum Reprod. 2012;27:303–13.PubMedGoogle Scholar
  77. Harvey MB, Kaye PL. Mediation of the actions of insulin and insulin-like growth factor-1 on preimplantation mouse embryos in vitro. Mol Reprod Dev. 1992;33:270–5.PubMedGoogle Scholar
  78. Heikkinen J, Mottonen M, Komi J, Alanen A, Lassila O. Phenotypic characterization of human decidual macrophages. Clin Exp Immunol. 2003;131:498–505.PubMedCentralPubMedGoogle Scholar
  79. Hill JA, Haimovici F, Anderson DJ. Products of activated lymphocytes and macrophages inhibit mouse embryo development in vitro. J Immunol. 1987;139:2250–4.PubMedGoogle Scholar
  80. Hill JA, Polgar K, Harlow BL, Anderson DJ. Evidence of embryo- and trophoblast-toxic cellular immune response(s) in women with recurrent spontaneous abortion. Am J Obstet Gynecol. 1992;166:1044–52.PubMedGoogle Scholar
  81. Hilton DJ, Nicola NA, Metcalf D. Specific binding of murine leukemia inhibitory factor to normal and leukemic monocytic cells. Proc Natl Acad Sci U S A. 1988;85:5971–5.PubMedCentralPubMedGoogle Scholar
  82. Hochberg Z, Feil R, Constancia M, Fraga M, Junien C, Carel JC, Boileau P, Le Bouc Y, Deal CL, Lillycrop K, Scharfmann R, Sheppard A, et al. Child health, developmental plasticity, and epigenetic programming. Endocr Rev. 2011;32:159–224.PubMedCentralPubMedGoogle Scholar
  83. Hunt JS. Expression and regulation of the tumour necrosis factor-alpha gene in the female reproductive tract. Reprod Fertil Dev. 1993;5:141–53.PubMedGoogle Scholar
  84. Hunt JS, Robertson SA. Uterine macrophages and environmental programming for pregnancy success. J Reprod Immunol. 1996;32:1–25.PubMedGoogle Scholar
  85. Hunt JS, Chen HL, Hu XL, Pollard JW. Normal distribution of tumor necrosis factor-alpha messenger ribonucleic acid and protein in the uteri, placentas, and embryos of osteopetrotic (op/op) mice lacking colony-stimulating factor-1. Biol Reprod. 1993;49:441–52.PubMedGoogle Scholar
  86. Imakawa K, Helmer SD, Nephew KP, Meka CS, Christenson RK. A novel role for GM-CSF: enhancement of pregnancy specific interferon production, ovine trophoblast protein-1. Endocrinology. 1993;132:1869–71.PubMedGoogle Scholar
  87. Ingman WV, Jones RL. Cytokine knockouts in reproduction: the use of gene ablation to dissect roles of cytokines in reproductive biology. Hum Reprod Update. 2008;14:179–92.PubMedGoogle Scholar
  88. Iwamoto GK, Konicek SA. Cytomegalovirus immediate early genes upregulate interleukin-6 gene expression. J Investig Med. 1997;45:175–82.PubMedGoogle Scholar
  89. Jin XL, O’Neill C. Regulation of the expression of proto-oncogenes by autocrine embryotropins in the early mouse embryo. Biol Reprod. 2011;84:1216–24.PubMedGoogle Scholar
  90. Jin XL, Chandrakanthan V, Morgan HD, O’Neill C. Preimplantation embryo development in the mouse requires the latency of TRP53 expression, which is induced by a ligand-activated PI3 kinase/AKT/MDM2-mediated signaling pathway. Biol Reprod. 2009;80:286–94.PubMedCentralPubMedGoogle Scholar
  91. Jokhi PP, King A, Sharkey AM, Smith SK, Loke YW. Screening for cytokine messenger ribonucleic acids in purified human decidual lymphocyte populations by the reverse- transcriptase polymerase chain reaction. J Immunol. 1994;153:4427–35.PubMedGoogle Scholar
  92. Jones RL, Hannan NJ, Kaitu’u TJ, Zhang J, Salamonsen LA. Identification of chemokines important for leukocyte recruitment to the human endometrium at the times of embryo implantation and menstruation. J Clin Endocrinol Metab. 2004;89:6155–67.PubMedGoogle Scholar
  93. Kafka JK, Sheth PM, Nazli A, Osborne BJ, Kovacs C, Kaul R, Kaushic C. Endometrial epithelial cell response to semen from HIV-infected men during different stages of infection is distinct and can drive HIV-1-long terminal repeat. AIDS. 2012;26:27–36.PubMedGoogle Scholar
  94. Kane MT, Morgan PM, Coonan C. Peptide growth factors and preimplantation development. Hum Reprod Update. 1997;3:137–57.PubMedGoogle Scholar
  95. Kanno Y, Vahedi G, Hirahara K, Singleton K, O’Shea JJ. Transcriptional and epigenetic control of T helper cell specification: molecular mechanisms underlying commitment and plasticity. Annu Rev Immunol. 2012;30:707–31.PubMedCentralPubMedGoogle Scholar
  96. Karagenc L, Lane M, Gardner DK. Granulocyte-macrophage colony-stimulating factor stimulates mouse blastocyst inner cell mass development only when media lack human serum albumin. Reprod Biomed Online. 2005;10:511–8.PubMedGoogle Scholar
  97. Kauma SW, Aukerman SL, Eierman D, Turner T. Colony-stimulating factor-1 and c-fms expression in human endometrial tissues and placenta during the menstrual cycle and early pregnancy. J Clin Endocrinol Metab. 1991;73:746–51.PubMedGoogle Scholar
  98. Kauma S, Huff T, Krystal G, Ryan J, Takacs P, Turner T. The expression of stem cell factor and its receptor, c-kit in human endometrium and placental tissues during pregnancy. J Clin Endocrinol Metab. 1996;81:1261–6.PubMedGoogle Scholar
  99. Kawamura K, Sato N, Fukuda J, Kodama H, Kumagai J, Tanikawa H, Nakamura A, Tanaka T. Leptin promotes the development of mouse preimplantation embryos in vitro. Endocrinology. 2002;143:1922–31.PubMedGoogle Scholar
  100. Kawamura K, Fukuda J, Shimizu Y, Kodama H, Tanaka T. Survivin contributes to the anti-apoptotic activities of transforming growth factor alpha in mouse blastocysts through phosphatidylinositol 3’-kinase pathway. Biol Reprod. 2005;73:1094–101.PubMedGoogle Scholar
  101. Kawamura K, Chen Y, Shu Y, Cheng Y, Qiao J, Behr B, Pera RA, Hsueh AJ. Promotion of human early embryonic development and blastocyst outgrowth in vitro using autocrine/paracrine growth factors. PLoS ONE. 2012;7:e49328.PubMedCentralPubMedGoogle Scholar
  102. Kaye PL. Preimplantation growth factor physiology. Rev Reprod. 1997;2:121–27.PubMedGoogle Scholar
  103. Kaye PL, Gardner HG. Preimplantation access to maternal insulin and albumin increases fetal growth rate in mice. Hum Reprod. 1999;14:3052–9.PubMedGoogle Scholar
  104. Kaye PL, Harvey MB. The role of growth factors in preimplantation development. Prog Growth Factor Res. 1995;6:1–24.PubMedGoogle Scholar
  105. Kelly RW, King AE, Critchley HO. Cytokine control in human endometrium. Reproduction. 2001;121:3–19.PubMedGoogle Scholar
  106. Kelso A. Cytokines: principles and prospects. Immunol Cell Biol. 1998;76:300–17.PubMedGoogle Scholar
  107. Kho EM, McCowan LM, North RA, Roberts CT, Chan E, Black MA, Taylor RS, Dekker GA. Duration of sexual relationship and its effect on preeclampsia and small for gestational age perinatal outcome. J Reprod Immunol. 2009;82:66–73.PubMedGoogle Scholar
  108. Khosla S, Dean W, Brown D, Reik W, Feil R. Culture of preimplantation mouse embryos affects fetal development and the expression of imprinted genes. Biol Reprod. 2001;64:918–26.PubMedGoogle Scholar
  109. Kimber SJ. Leukaemia inhibitory factor in implantation and uterine biology. Reproduction. 2005;130:131–45.PubMedGoogle Scholar
  110. Kimber SJ, Sneddon SF, Bloor DJ, El-Bareg AM, Hawkhead JA, Metcalfe AD, Houghton FD, Leese HJ, Rutherford A, Lieberman BA, Brison DR. Expression of genes involved in early cell fate decisions in human embryos and their regulation by growth factors. Reproduction. 2008;135:635–47.PubMedGoogle Scholar
  111. Kittan NA, Allen RM, Dhaliwal A, Cavassani KA, Schaller M, Gallagher KA, Carson WFt, Mukherjee S, Grembecka J, Cierpicki T, Jarai G, Westwick J, et al. Cytokine induced phenotypic and epigenetic signatures are key to establishing specific macrophage phenotypes. PLoS ONE. 2013;8:e78045.PubMedCentralPubMedGoogle Scholar
  112. Kwong WY, Wild AE, Roberts P, Willis AC, Fleming TP. Maternal undernutrition during the preimplantation period of rat development causes blastocyst abnormalities and programming of postnatal hypertension. Development. 2000;127:4195–202.PubMedGoogle Scholar
  113. Lachapelle MH, Miron P, Hemmings R, Falcone T, Granger L, Bourque J, Langlais J. Embryonic resistance to tumour necrosis factor-alpha mediated cytotoxicity: novel mechanism underlying maternal immunological tolerance to the fetal allograft. Hum Reprod. 1993;8:1032–8.PubMedGoogle Scholar
  114. Leese HJ. Metabolism of the preimplantation embryo: 40 years on. Reproduction. 2012;143:417–27.PubMedGoogle Scholar
  115. Leonard WJ. Role of Jak kinases and STATs in cytokine signal transduction. Int J Hematol. 2001;73:271–7.PubMedGoogle Scholar
  116. Leonard WJ, O’Shea JJ. Jaks and STATs: biological implications. Annu Rev Immunol. 1998;16:293–322.PubMedGoogle Scholar
  117. Li Y, Chandrakanthan V, Day ML, O’Neill C. Direct evidence for the action of phosphatidylinositol (3,4,5)-trisphosphate-mediated signal transduction in the 2-cell mouse embryo. Biol Reprod. 2007;77:813–21.PubMedGoogle Scholar
  118. Lighten AD, Hardy K, Winston RM, Moore GE. Expression of mRNA for the insulin-like growth factors and their receptors in human preimplantation embryos. Mol Reprod Dev. 1997;47:134–9.PubMedGoogle Scholar
  119. Lighten AD, Moore GE, Winston RM, Hardy K. Routine addition of human insulin-like growth factor-I ligand could benefit clinical in-vitro fertilization culture. Hum Reprod. 1998;13:3144–50.PubMedGoogle Scholar
  120. Lim HJ, Dey SK. HB-EGF: a unique mediator of embryo-uterine interactions during implantation. Exp Cell Res. 2009;315:619–26.PubMedCentralPubMedGoogle Scholar
  121. Lim JJ, Eum JH, Lee JE, Kim ES, Chung HM, Yoon TK, Kim KS, Lee DR. Stem cell factor/c-Kit signaling in in vitro cultures supports early mouse embryonic development by accelerating proliferation via a mechanism involving Akt-downstream genes. J Assist Reprod Genet. 2010;27:619–27.PubMedCentralPubMedGoogle Scholar
  122. Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell. 1993;75:59–72.PubMedGoogle Scholar
  123. Liu JL, Yakar S, LeRoith D. Conditional knockout of mouse insulin-like growth factor-1 gene using the Cre/loxP system. Proc Soc Exp Biol Med. 2000;223:344–51.PubMedGoogle Scholar
  124. Lotti F, Corona G, Colpi GM, Filimberti E, Degli Innocenti S, Mancini M, Baldi E, Noci I, Forti G, Adorini L, Maggi M. Elevated body mass index correlates with higher seminal plasma interleukin 8 levels and ultrasonographic abnormalities of the prostate in men attending an andrology clinic for infertility. J Endocrinol Invest. 2011;34:e336–e42.PubMedGoogle Scholar
  125. Loureiro B, Bonilla L, Block J, Fear JM, Bonilla AQ, Hansen PJ. Colony-stimulating factor 2 (CSF-2) improves development and posttransfer survival of bovine embryos produced in vitro. Endocrinology. 2009;150:5046–54.PubMedCentralPubMedGoogle Scholar
  126. Maher ER, Afnan M, Barratt CL. Epigenetic risks related to assisted reproductive technologies: epigenetics, imprinting, ART and icebergs? Hum Reprod. 2003;18:2508–11.PubMedGoogle Scholar
  127. Malinin NL, Boldin MP, Kovalenko AV, Wallach D. MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1. Nature. 1997;385:540–4.PubMedGoogle Scholar
  128. Markham KE, Kaye PL. Growth hormone, insulin-like growth factor I and cell proliferation in the mouse blastocyst. Reproduction. 2003;125:327–36.PubMedGoogle Scholar
  129. Martal J, Chene N, Camous S, Huynh L, Lantier F, Hermier P, L’Haridon R, Charpigny G, Charlier M, Chaouat G. Recent developments and potentialities for reducing embryo mortality in ruminants: the role of IFN-tau and other cytokines in early pregnancy. Reprod Fertil Dev. 1997;9:355–80.PubMedGoogle Scholar
  130. Martin KL, Barlow DH, Sargent IL. Heparin-binding epidermal growth factor significantly improves human blastocyst development and hatching in serum-free medium. Hum Reprod. 1998;13:1645–52.PubMedGoogle Scholar
  131. Michael DD, Wagner SK, Ocon OM, Talbot NC, Rooke JA, Ealy AD. Granulocyte-macrophage colony-stimulating-factor increases interferon-tau protein secretion in bovine trophectoderm cells. Am J Reprod Immunol. 2006;56:63–7.PubMedGoogle Scholar
  132. Mikaelsson MA, Constancia M, Dent CL, Wilkinson LS, Humby T. Placental programming of anxiety in adulthood revealed by Igf2-null models. Nat Commun. 2013;4:2311.PubMedGoogle Scholar
  133. Mitchell MH, Swanson RJ, Oehninger S. In vivo effect of leukemia inhibitory factor (LIF) and an anti-LIF polyclonal antibody on murine embryo and fetal development following exposure at the time of transcervical blastocyst transfer. Biol Reprod. 2002;67:460–4.PubMedGoogle Scholar
  134. Mitsuyama K, Suzuki A, Tomiyasu N, Takaki K, Toyonaga A, Sata M. Transcription factor-targeted therapies in inflammatory bowel disease. Digestion. 2001;63(Suppl 1):68–72.PubMedGoogle Scholar
  135. Morgan HD, Santos F, Green K, Dean W, Reik W. Epigenetic reprogramming in mammals. Hum Mol Genet. 2005;14(Spec No 1):R47–R58.PubMedGoogle Scholar
  136. Morita Y, Tsutsumi O, Taketani Y. In vitro treatment of embryos with epidermal growth factor improves viability and increases the implantation rate of blastocysts transferred to recipient mice. Am J Obstet Gynecol. 1994;171:406–9.PubMedGoogle Scholar
  137. Murray R, Lee F, Chiu CP. The genes for leukemia inhibitory factor and interleukin-6 are expressed in mouse blastocysts prior to the onset of hemopoiesis. Mol Cell Biol. 1990;10:4953–6.PubMedCentralPubMedGoogle Scholar
  138. Murphy SP, Tayade C, Ashkar AA, Hatta K, Zhang J, Croy BA. Interferon gamma in successful pregnancies. Biol Reprod. 2009;80:848–59.PubMedCentralPubMedGoogle Scholar
  139. Nakasato M, Shirakura Y, Ooga M, Iwatsuki M, Ito M, Kageyama S-i, Sakai S, Nagata M, Aoki F. Involvement of the STAT5 signaling pathway in the regulation of mouse preimplantation development. Biol Reprod. 2006;75:508–17.PubMedGoogle Scholar
  140. Natale DR, Paliga AJ, Beier F, D’Souza SJ, Watson AJ. p38 MAPK signaling during murine preimplantation development. Dev Biol. 2004;268:76–88.PubMedGoogle Scholar
  141. Nathan C, Sporn M. Cytokines in context. J Cell Biol. 1991;113:981–6.PubMedGoogle Scholar
  142. Nichols J, Davidson D, Taga T, Yoshida K, Chambers I, Smith A. Complementary tissue-specific expression of LIF and LIF-receptor mRNAs in early mouse embryogenesis. Mech Dev. 1996;57:123–31.PubMedGoogle Scholar
  143. Nicola NA. Guidebook to cytokines and their receptors. Oxford: Oxford University Press; 1994.Google Scholar
  144. Norwitz ER, Schust DJ, Fisher SJ. Implantation and the survival of early pregnancy. N Engl J Med. 2001;345:1400–8.PubMedGoogle Scholar
  145. O’Neill C. Evidence for the requirement of autocrine growth factors for development of mouse preimplantation embryos in vitro. Biol Reprod 1997;56:229–37.PubMedGoogle Scholar
  146. O’Neill C. The potential roles for embryotrophic ligands in preimplantation embryo development. Hum Reprod Update. 2008;14:275–88.PubMedGoogle Scholar
  147. O’Neill C, Li Y, Jin XL. Survival signaling in the preimplantation embryo. Theriogenology. 2012;77:773–84.PubMedGoogle Scholar
  148. Ono K, Han J. The p38 signal transduction pathway: activation and function. Cell Signal. 2000;12:1–13.PubMedGoogle Scholar
  149. Osaki M, Oshimura M, Ito H. PI3K-Akt pathway: its functions and alterations in human cancer. Apoptosis. 2004;9:667–76.PubMedGoogle Scholar
  150. Paliga AJ, Natale DR, Watson AJ. p38 mitogen-activated protein kinase (MAPK) first regulates filamentous actin at the 8–16-cell stage during preimplantation development. Biol Cell. 2005;97:629–40.PubMedGoogle Scholar
  151. Pampfer S, Arceci RJ, Pollard JW. Role of colony stimulating factor-1 (CSF-1) and other lympho-hematopoietic growth factors in mouse pre-implantation development. Bioessays. 1991;13:535–40.PubMedGoogle Scholar
  152. Pampfer S, Moulaert B, Vanderheyden I, Wuu YD, De Hertogh R. Effect of tumour necrosis factor alpha on rat blastocyst growth and glucose metabolism. J Reprod Fertil. 1994a;101:199–206.PubMedGoogle Scholar
  153. Pampfer S, Wuu YD, Vanderheyden I, De Hertogh R. Expression of tumor necrosis factor-alpha (TNF alpha) receptors and selective effect of TNF alpha on the inner cell mass in mouse blastocysts. Endocrinology. 1994b;134:206–12.PubMedGoogle Scholar
  154. Pampfer S, Vanderheyden I, McCracken JE, Vesela J, De Hertogh R. Increased cell death in rat blastocysts exposed to maternal diabetes in utero and to high glucose or tumor necrosis factor-alpha in vitro. Development. 1997;124:4827–36.PubMedGoogle Scholar
  155. Paria BC, Dey SK. Preimplantation embryo development in vitro: cooperative interactions among embryos and role of growth factors. Proc Natl Acad Sci U S A. 1990;87:4756–60.PubMedCentralPubMedGoogle Scholar
  156. Paria BC, Ma W, Tan J, Raja S, Das SK, Dey SK, Hogan BL. Cellular and molecular responses of the uterus to embryo implantation can be elicited by locally applied growth factors. Proc Natl Acad Sci U S A. 2001;98:1047–52.PubMedCentralPubMedGoogle Scholar
  157. Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, Cobb MH. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev. 2001;22:153–83.PubMedGoogle Scholar
  158. Perugini M, Brown AL, Salerno DG, Booker GW, Stojkoski C, Hercus TR, Lopez AF, Hibbs ML, Gonda TJ, D’Andrea RJ. Alternative modes of GM-CSF receptor activation revealed using activated mutants of the common beta-subunit. Blood. 2010;115:3346–53.PubMedCentralPubMedGoogle Scholar
  159. Petroff MG, Sedlmayr P, Azzola D, Hunt JS. Decidual macrophages are potentially susceptible to inhibition by class Ia and class Ib HLA molecules. J Reprod Immunol. 2002;56:3–17.PubMedGoogle Scholar
  160. Pfeifer TL, Chegini N. Immunohistochemical localization of insulin-like growth factor (IGF-I), IGF-I receptor, and IGF binding proteins 1–4 in human fallopian tube at various reproductive stages. Biol Reprod. 1994;50:281–9.PubMedGoogle Scholar
  161. Piccinni MP, Romagnani S. Regulation of fetal allograft survival by a hormone-controlled Th1- and Th2-type cytokines. Immunol Res. 1996;15:141–50.PubMedGoogle Scholar
  162. Pollard JW, Bartocci A, Arceci R, Orlofsky A, Ladner MB, Stanley ER. Apparent role of the macrophage growth factor CSF-1, in placental development. Nature. 1987;330:484–6.PubMedGoogle Scholar
  163. Pollard JW. Role of cytokines in the pregnant uterus of interstitial implanting species. In: Bazer FW, editor. The endocrinology of pregnancy. Totowa: Humana Press Inc.; 1998. pp. 59–82.Google Scholar
  164. Raab G, Kover K, Paria BC, Dey SK, Ezzell RM, Klagsbrun M. Mouse preimplantation blastocysts adhere to cells expressing the transmembrane form of heparin-binding EGF-like growth factor. Development. 1996;122:637–45.PubMedGoogle Scholar
  165. Rappolee DA, Sturm KS, Behrendtsen O, Schultz GA, Pedersen RA, Werb Z. Insulin-like growth factor II acts through an endogenous growth pathway regulated by imprinting in early mouse embryos. Genes Dev. 1992;6:939–52.PubMedGoogle Scholar
  166. Rasmussen SJ, Eckmann L, Quayle AJ, Shen L, Zhang YX, Anderson DJ, Fierer J, Stephens RS, Kagnoff MF. Secretion of proinflammatory cytokines by epithelial cells in response to Chlamydia infection suggests a central role for epithelial cells in chlamydial pathogenesis. J Clin Invest. 1997;99:77–87.PubMedCentralPubMedGoogle Scholar
  167. Richter KS. The importance of growth factors for preimplantation embryo development and in-vitro culture. Curr Opin Obstet Gynecol. 2008;20:292–304.PubMedGoogle Scholar
  168. Riley JK, Heeley JM, Wyman AH, Schlichting EL, Moley KH. TRAIL and KILLER are expressed and induce apoptosis in the murine preimplantation embryo. Biol Reprod. 2004;71:871–7.PubMedGoogle Scholar
  169. Robertson SA. Seminal plasma and male factor signalling in the female reproductive tract. Cell Tissue Res. 2005;322:43–52.PubMedGoogle Scholar
  170. Robertson SA. GM-CSF regulation of embryo development and pregnancy. Cytokine Growth Factor Rev. 2007;18:287–98.PubMedGoogle Scholar
  171. Robertson SA. Immune regulation of conception and embryo implantation-all about quality control? J Reprod Immunol. 2010;85:51–57.PubMedGoogle Scholar
  172. Robertson SA, Seamark RF. Granulocyte-macrophage colony stimulating factor (GM-CSF): one of a family of epithelial cell-derived cytokines in the preimplantation uterus. Reprod Fertil Dev. 1992;4:435–48.PubMedGoogle Scholar
  173. Robertson SA, Lavranos TC, Seamark RF. In vitro models of the maternal fetal interface. In: Wegmann TG, Nisbett-Brown E, Gill TG, editors. The molecular and cellular immunobiology of the maternal-fetal interface. New York: Oxford University Press; 1991. pp. 191–206.Google Scholar
  174. 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;46:1069–79.PubMedGoogle Scholar
  175. Robertson M, Chambers I, Rathjen P, Nichols J, Smith A. Expression of alternative forms of differentiation inhibiting activity (DIA/LIF) during murine embryogenesis and in neonatal and adult tissues. Dev Genet. 1993;14:165–73.PubMedGoogle Scholar
  176. Robertson SA, Seamark RF, Guilbert LJ, Wegmann TG. The role of cytokines in gestation. Crit Rev Immunol. 1994;14:239–92.PubMedGoogle Scholar
  177. 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;54:183–96.PubMedGoogle Scholar
  178. Robertson SA, Roberts CT, Farr KL, Dunn AR, Seamark RF. Fertility impairment in granulocyte-macrophage colony-stimulating factor-deficient mice. Biol Reprod. 1999;60:251–61.PubMedGoogle Scholar
  179. Robertson SA, Sjoblom C, Jasper MJ, Norman RJ, Seamark RF. Granulocyte-macrophage colony-stimulating factor promotes glucose transport and blastomere viability in murine preimplantation embryos. Biol Reprod. 2001;64:1206–15.PubMedGoogle Scholar
  180. Robertson SA, Chin PY, Glynn DJ, Thompson JG. Peri-conceptual cytokines–setting the trajectory for embryo implantation, pregnancy and beyond. Am J Reprod Immunol. 2011;66(Suppl 1):2–10.PubMedGoogle Scholar
  181. Ruef C, Coleman DL. Granulocyte-macrophage colony-stimulating factor: pleiotropic cytokine with potential clinical usefulness. Rev Infect Dis. 1990;12:41–62.PubMedGoogle Scholar
  182. Sakagami N, Umeki H, Nishino O, Uchiyama H, Ichikawa K, Takeshita K, Kaneko E, Akiyama K, Kobayashi S, Tamada H. Normal calves produced after transfer of embryos cultured in a chemically defined medium supplemented with epidermal growth factor and insulin-like growth factor i following ovum pick up and in vitro fertilization in japanese black cows. J Reprod Dev. 2011;58(1):140–6.PubMedGoogle Scholar
  183. Salamonsen LA, Dimitriadis E, Robb L. Cytokines in implantation. Semin Reprod Med. 2000;18:299–310.PubMedGoogle Scholar
  184. Schaefer TM, Fahey JV, Wright JA, Wira CR. Innate immunity in the human female reproductive tract: antiviral response of uterine epithelial cells to the TLR3 agonist poly(I:C). J Immunol. 2005;174:992–1002.PubMedGoogle Scholar
  185. Schieve LA, Meikle SF, Ferre C, Peterson HB, Jeng G, Wilcox LS. Low and very low birth weight in infants conceived with use of assisted reproductive technology. N Engl J Med. 2002;346:731–7.PubMedGoogle Scholar
  186. Shao R, Egecioglu E, Weijdegard B, Kopchick JJ, Fernandez-Rodriguez J, Andersson N, Billig H. Dynamic regulation of estrogen receptor-alpha isoform expression in the mouse fallopian tube: mechanistic insight into estrogen-dependent production and secretion of insulin-like growth factors. Am J Physiol Endocrinol Metab. 2007;293:E1430–42.PubMedGoogle Scholar
  187. Sharkey AM, Dellow K, Blayney M, Macnamee M, Charnock-Jones S, Smith SK. Stage-specific expression of cytokine and receptor messenger ribonucleic acids in human preimplantation embryos. Biol Reprod. 1995;53:974–81.PubMedGoogle Scholar
  188. Sharkey DJ, Macpherson AM, Tremellen KP, Robertson SA. Seminal plasma differentially regulates inflammatory cytokine gene expression in human cervical and vaginal epithelial cells. Mol Hum Reprod. 2007;13:491–01.PubMedGoogle Scholar
  189. Sharkey DJ, Tremellen KP, Jasper MJ, Gemzell-Danielsson K, Robertson SA. Seminal fluid induces leukocyte recruitment and cytokine and chemokine mRNA expression in the human cervix after coitus. J Immunol. 2012;188:2445–54.PubMedGoogle Scholar
  190. Shen XH, Han YJ, Zhang DX, Cui XS, Kim NH. A link between the interleukin-6/Stat3 anti-apoptotic pathway and microRNA-21 in preimplantation mouse embryos. Mol Reprod Dev. 2009;76:854–62.PubMedGoogle Scholar
  191. Sjoblom C, Wikland M, Robertson SA. Granulocyte-macrophage colony-stimulating factor promotes human blastocyst development in vitro. Hum Reprod. 1999;14:3069–76.PubMedGoogle Scholar
  192. Sjoblom C, Wikland M, Robertson SA. Granulocyte-macrophage colony-stimulating factor (GM-CSF) acts independently of the beta common subunit of the GM-CSF receptor to prevent inner cell mass apoptosis in human embryos. Biol Reprod. 2002;67:1817–23.PubMedGoogle Scholar
  193. Sjoblom C, Roberts CT, Wikland M, Robertson SA. Granulocyte-macrophage colony-stimulating factor alleviates adverse consequences of embryo culture on fetal growth trajectory and placental morphogenesis. Endocrinology. 2005;146:2142–53.PubMedGoogle Scholar
  194. Smith RM, Garside WT, Aghayan M, Shi CZ, Shah N, Jarett L, Heyner S. Mouse preimplantation embryos exhibit receptor-mediated binding and transcytosis of maternal insulin-like growth factor I. Biol Reprod. 1993;49:1–12.PubMedGoogle Scholar
  195. Song H, Lim H, Das SK, Paria BC, Dey SK. Dysregulation of EGF family of growth factors and COX-2 in the uterus during the preattachment and attachment reactions of the blastocyst with the luminal epithelium correlates with implantation failure in LIF- deficient mice. Mol Endocrinol. 2000;14:1147–61.PubMedGoogle Scholar
  196. Spandorfer SD, Barmat LI, Liu HC, Mele C, Veeck L, Rosenwaks Z. Granulocyte macrophage-colony stimulating factor production by autologous endometrial co-culture is associated with outcome for in vitro fertilization patients with a history of multiple implantation failures. Am J Reprod Immunol. 1998;40:377–81.PubMedGoogle Scholar
  197. Stewart CL, Cullinan EB. Preimplantation development of the mammalian embryo and its regulation by growth factors. Dev Genet. 1997;21:91–101.PubMedGoogle Scholar
  198. Stewart CL, Kaspar P, Brunet LJ, Bhatt H, Gadi I, Kontgen F, Abbondanzo SJ. Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor. Nature. 1992;359:76–9.PubMedGoogle Scholar
  199. Strandell A, Thorburn J, Wallin A. The presence of cytokines and growth factors in hydrosalpingeal fluid. J Assist Reprod Genet. 2004;21:241–7.PubMedCentralPubMedGoogle Scholar
  200. Stratikopoulos E, Szabolcs M, Dragatsis I, Klinakis A, Efstratiadis A. The hormonal action of IGF1 in postnatal mouse growth. Proc Natl Acad Sci U S A. 2008;105:19378–83.PubMedCentralPubMedGoogle Scholar
  201. Sun XX, Gemzell-Danielsson K, Li HZ, Stabi B, Stavreus-Evers A. Expression of heparin-binding epidermal growth factor-like growth factor and its receptors in the human fallopian tube and endometrium after treatment with mifepristone. Fertil Steril. 2006;85:171–8.PubMedGoogle Scholar
  202. Tabibzadeh S. Role of cytokines in endometrium and at the fetomaternal interface. Reprod Med Rev. 1994;3:11–28.Google Scholar
  203. Tabibzadeh S, Sun XZ. Cytokine expression in human endometrium throughout the menstrual cycle. Human Reprod. 1992;7:1214–21.Google Scholar
  204. Teklenburg G, Salker M, Heijnen C, Macklon NS, Brosens JJ. The molecular basis of recurrent pregnancy loss: impaired natural embryo selection. Mol Hum Reprod. 2010;16:886–95.PubMedGoogle Scholar
  205. Thompson JG, Kind KL, Roberts CT, Robertson SA, Robinson JS. Epigenetic risks related to assisted reproductive technologies: short- and long-term consequences for the health of children conceived through assisted reproduction technology: more reason for caution? Hum Reprod. 2002;17:2783–6.PubMedGoogle Scholar
  206. Thompson JG, Lane M, Robertson SA. Adaptive responses of embryos to their microenvironment and consequences for post-implantation development. In: Owens JS, Wintour M, editors. Early life origins of health and disease: Advances in Experimental Medicine and Biology, Springer / Landes Bioscience 2006; 573:58-69 pp. 58–69.Google Scholar
  207. Tremellen KP, Valbuena D, Landeras J, Ballesteros A, Martinez J, Mendoza S, Norman RJ, Robertson SA, Simon C. The effect of intercourse on pregnancy rates during assisted human reproduction. Hum Reprod. 2000;15:2653–8.PubMedGoogle Scholar
  208. Truchet S, Wietzerbin J, Debey P. Mouse oocytes and preimplantation embryos bear the two sub-units of interferon-gamma receptor. Mol Reprod Dev. 2001;60:319–30.PubMedGoogle Scholar
  209. Truchet S, Chebrout M, Djediat C, Wietzerbin J, Debey P. Presence of permanently activated signal transducers and activators of transcription in nuclear interchromatin granules of unstimulated mouse oocytes and preimplantation embryos. Biol Reprod. 2004;71:1330–9.PubMedGoogle Scholar
  210. Tzanavari T, Giannogonas P, Karalis KP. TNF-alpha and obesity. Curr Dir Autoimmun. 2010;11:145–56.PubMedGoogle Scholar
  211. Wang J, Mayernik L, Schultz JF, Armant DR. Acceleration of trophoblast differentiation by heparin-binding EGF-like growth factor is dependent on the stage-specific activation of calcium influx by ErbB receptors in developing mouse blastocysts. Development. 2000;127:33–44.PubMedGoogle Scholar
  212. Wang Y, Wang F, Sun T, Trostinskaia A, Wygle D, Puscheck E, Rappolee DA. Entire mitogen activated protein kinase (MAPK) pathway is present in preimplantation mouse embryos. Dev Dyn. 2004;231:72–87.Ware CB, Horowitz MC, Renshaw BR, Hunt JS, Liggitt D, Koblar SA, Gliniak BC, McKenna HJ, Papayannopoulou T, Thoma B, et al (1995): Targeted disruption of the low-affinity leukemia inhibitory factor receptor gene causes placental, skeletal, neural and metabolic defects and results in perinatal death. Development 1995;121:1283-1299.PubMedGoogle Scholar
  213. Williams CL, Teeling JL, Perry VH, Fleming TP. Mouse maternal systemic inflammation at the zygote stage causes blunted cytokine responsiveness in lipopolysaccharide-challenged adult offspring. BMC Biol. 2011;9:49.PubMedCentralPubMedGoogle Scholar
  214. Woodgett JR, Avruch J, Kyriakis J. The stress activated protein kinase pathway. Cancer Surv. 1996;27:127–38.PubMedGoogle Scholar
  215. Wuu YD, Pampfer S, Becquet P, Vanderheyden I, Lee KH, De Hertogh R. Tumor necrosis factor alpha decreases the viability of mouse blastocysts in vitro and in vivo. Biol Reprod. 1999;60:479–83.PubMedGoogle Scholar
  216. Xie Y, Puscheck EE, Rappolee DA. Effects of SAPK/JNK inhibitors on preimplantation mouse embryo development are influenced greatly by the amount of stress induced by the media. Mol Hum Reprod. 2006;12:217–24.PubMedGoogle Scholar
  217. Xie H, Wang H, Tranguch S, Iwamoto R, Mekada E, Demayo FJ, Lydon JP, Das SK, Dey SK. Maternal heparin-binding-EGF deficiency limits pregnancy success in mice. Proc Natl Acad Sci U S A. 2007;104:18315–20.PubMedCentralPubMedGoogle Scholar
  218. Xie Y, Liu J, Proteasa S, Proteasa G, Zhong W, Wang Y, Wang F, Puscheck EE, Rappolee DA. Transient stress and stress enzyme responses have practical impacts on parameters of embryo development, from IVF to directed differentiation of stem cells. Mol Reprod Dev. 2008;75:689–97.PubMedGoogle Scholar
  219. Yeaman GR, Collins JE, Currie JK, Guyre PM, Wira CR, Fanger MW. IFN-gamma is produced by polymorphonuclear neutrophils in human uterine endometrium and by cultured peripheral blood polymorphonuclear neutrophils. J Immunol. 1998;160:5145–53.PubMedGoogle Scholar
  220. Young LE. Imprinting of genes and the Barker hypothesis. Twin Res. 2001;4:307–17.PubMedGoogle Scholar
  221. Young LE, Fernandes K, McEvoy TG, Butterwith SC, Gutierrez CG, Carolan C, Broadbent PJ, Robinson JJ, Wilmut I, Sinclair KD. Epigenetic change in IGF2R is associated with fetal overgrowth after sheep embryo culture. Nat Genet. 2001;27:153–4.PubMedGoogle Scholar
  222. Zhang X, Armstrong DT. Presence of amino acids and insulin in a chemically defined medium improves development of 8-cell rat embryos in vitro and subsequent implantation in vivo. Biol Reprod. 1990;42:662–8.PubMedGoogle Scholar
  223. Zhang X, Kidder GM, Watson AJ, Schultz GA, Armstrong DT. Possible roles of insulin and insulin-like growth factors in rat preimplantation development: investigation of gene expression by reverse transcription-polymerase chain reaction. J Reprod Fertil. 1994;100:375–80.PubMedGoogle Scholar
  224. Zhang J, Lathbury LJ, Salamonsen LA. Expression of the chemokine eotaxin and its receptor, CCR3, in human endometrium. Biol Reprod. 2000;62:404–11.PubMedGoogle Scholar
  225. Zhao Y, Chegini N, Flanders KC. Human fallopian tube expresses transforming growth factor (TGF beta) isoforms, TGF beta type I-III receptor messenger ribonucleic acid and protein, and contains [125I]TGF beta-binding sites. J Clin Endocrinol Metab. 1994;79:1177–84.PubMedGoogle Scholar
  226. Zhao XY, Sakashita K, Kamijo T, Hidaka E, Sugane K, Kubota T, Koike K. Granulocyte-macrophage colony-stimulating factor induces de novo methylation of the p15 CpG island in hematopoietic cells. Cytokine. 2005;31:203–12.PubMedGoogle Scholar
  227. Zhong W, Sun T, Wang QT, Wang Y, Xie Y, Johnson A, Leach R, Puscheck EE, Rappolee DA. SAPKgamma/JNK1 and SAPKalpha/JNK2 mRNA transcripts are expressed in early gestation human placenta and mouse eggs, preimplantation embryos, and trophoblast stem cells. Fertil Steril. 2004;82(Suppl 3):1140–8.PubMedGoogle Scholar
  228. Zhou G, Bao ZQ, Dixon JE. Components of a new human protein kinase signal transduction pathway. J Biol Chem. 1995;270:12665–9.PubMedGoogle Scholar
  229. Ziebe S, Loft A, Povlsen BB, Erb K, Agerholm I, Aasted M, Gabrielsen A, Hnida C, Zobel DP, Munding B, Bendz SH, Robertson SA. A randomized clinical trial to evaluate the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) in embryo culture medium for in vitro fertilization. Fertil Steril. 2013;99:1600–9.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Sarah A. Robertson
    • 1
    Email author
  • Peck-Yin Chin
    • 1
  • John E. Schjenken
    • 1
  • Jeremy G. Thompson
    • 1
  1. 1.The Robinson Research Institute, School of Paediatrics and Reproductive HealthUniversity of AdelaideAdelaideAustralia

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