It is now accepted that local changes to the balance of Th1/Th2-type cytokines occur during pregnancy within the maternal uterus and fetoplacental unit. These changes in cytokine profiles contribute to implantation of the embryo, development of the placenta, and survival of the fetus to term. Overall within the placenta there is a bias in the ratio of Th1:Th2 cytokines towards the Th2-type cytokines. However, there are specific fluctuations in this balance at implantation and during the initiation of parturition. The predominant cytokines at each stage of gestation function both to limit maternal immune rejection of the semi-allogeneic embryo/fetus, especially at the maternofetal interface; and to facilitate the on-going physiological processes within the maternal reproductive tract. These two, at times conflicting, roles are discussed in this review, with key evidence concerning cytokine expression and function from mouse and humans.

Loke YW, King A: Human Implantation. Cell Biology and Immunology. Cambridge, Cambridge University Press, 1995.
Sanchez-Cuenca J, Martin JC, Pellicer A, Simon C: Cytokine pleiotropy and redundancy – gp130 cytokines in human implantation. Immunol Today 1999;20:57–59.
Raghupathy R: Th1-type immunity is incompatible with successful pregnancy. Immunol Today 1997;18:478–482.
Chard T: Cytokines in implantation. Hum Reprod Update 1995;1:385–396.
Huleihel M, Lunenfeld E, Horowitz S, Levy A, Potashnik G, Mazor M, Glezerman R: Involvement of serum and lipopolysaccharide in the production of interleukin-1 and interleukin-6-like molecules by human sperm cells. Am J Reprod Immunol 2000;43:41–46.
Chu TM, Nocera M, Flanders KC, Kawinski E: Localisation of seminal plasma transforming growth factor-beta(1) on human spermatozoa: An immunocytochemical study. Fertil Steril 1996;66:327–330.
de Mola JRL, Goldfarb JM, Hecht BR, Baumgardner GP, Babbo CJ, Friedlander MA: Gonadotropins induce the release of interleukin-1 beta, interleukin-6 and tumor necrosis factor-alpha from the human preovulatory follicle. Am J Reprod Immunol 1998;39:387–390.
Kutteh WH, Moldoveanu Z, Mestecky J: Mucosal immunity in the female reproductive tract: Correlation of immunoglobulins, cytokines and reproductive hormones in human cervical mucus around the time of ovulation. AIDS Res Hum Retroviruses 1998;14:S51–S55.
Cullinan EB, Abbondanzo SJ, Anderson PS, Pollard JW, Lessey BA, Stewart CL: Leukemia inhibitory factor (LIF) and LIF receptor expression in human endometrium suggests a potential autocrine paracrine function in regulating embryo implantation. Proc Natl Acad Sci USA 1996;93:3115–3120.
Sharkey AM, Clark DE, Burrows TD, Johki PP, Charnock-Jones DS, Loke YW, Smith SK: Localisation of leukemia inhibitory factor and its receptor in human placenta throughout pregnancy. Biol Reprod 2000;60:355–364.
Robb L, Li R, Hartley L, Nandurkar HH, Koentgen F, Begley CG: Infertility in female mice lacking the receptor for interleukin 11 is due to a defective uterine response to implantation. Nat Med 1998;4:303–308.
Simon C, Moreno C, Remohi J, Pellicer A: Cytokines and embryo implantation. J Reprod Immunol 1998;39:117–131.
Robertson SA, Roberts CT, Farr KL, Dunn AR, Seamark RF: Fertility impairment in granulocyte-macrophage colony-stimulating factor-deficient mice. Biol Reprod 1999;60:251–261.
Clark DE, Smith SK, Licence D, Evans AL, Charnock-Jones DS: Comparison of expression patterns for placenta growth factor, vascular endothelial growth factor (VEGF), VEGF-B and VEGF-C in the human placenta throughout gestation. J Endocrinol 1998;159:459–467.
Mosmann TR, Sad S: The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today 1996;17:138–146.
Vassiliadou N, Bulmer JN: Quantitiative analysis of T lymphocyte subsets in pregnant and nonpregnant human endometrium. Biol Reprod 1996;55:1017–1022.
Hunt JS, Petroff MG, Burnett TG: Uterine leukocytes: Key players in pregnancy. Semin Cell Dev Biol 2000;11:127–137.
Wegmann TG, Lin H, Giulbert L, Mosmann TR: Bidirectional cytokine interactions in the maternal-fetal relationship: Is successful pregnancy a Th2 phenomenon? Immunol Today 1993;14:353–356.
Guilbert LJ: There is a bias against type 1 (inflammatory) cytokine expression and function in pregnancy. J Reprod Immunol 1996;32:105–110.
Sacks G, Sargent I, Redman C: An innate view of human pregnancy. Immunol Today 1999;20:114–118.
Bonney EA, Matzinger P: The maternal immune system’s interaction with circulating fetal cells. J Immunol 1997;158:40–47.
Kelly RW, Critchley HOD: A T-helper-2 bias in decidua: The prostaglandin contribution of the macrophage and trophoblast. J Reprod Immunol 1997;33:181–187.
Kraan TCTMV, Boeije LCM, Smeenk RJT, Wijdenes J, Aarden LA: Prostaglandin-E2 is a potent inhibitor of human interleukin-12 production. J Exp Med 1995;181:775–779.
Kelly RW, Critchley HOD: T-cell modulation in decidua. Immunol Today 1998;19:142–143.
Krishnan L, Guilbert LJ, Russell AS, Wegmann TG, Mosmann TG, Belosevic M: Pregnancy impairs resistance of C57BL/6 mice to Leishmania major infection and causes decreased antigen-specific IFNγ responses and increased production of T helper 2 cytokines. J Immunol 1996;156:644–652.
Krishnan L, Guilbert LJ, Wegmann TG, Belosevic M, Mosmann TG: T helper 1 response against Leishmania major in pregnant C57BL/6 mice increases implantation failure and fetal resorptions. J Immunol 1996;156:653–662.
Chaouat G, Meliani AA, Martal J, Raghupathy R, Elliot J, Mosmann T, Wegmann TG: IL-10 prevents naturally occurring fetal loss in the CBA × DBA/2 mating combination, and local defect in IL-10 production in this abortion-prone combination is corrected by in vivo injection of IFNτ. J Immunol 1995;154:4261–4268.
Clark DA, Chaouat G, Arck PC, Mittruecker HW, Levy GA: Cytokine-dependent abortion in CBA × DBA/2 mice is mediated by the procoagulant fgl2 prothrombinase. J Immunol 1998;160:545–549.
Saito S, Tsukaguchi N, Hasegawa T, Michimata T, Tsuda H, Narita N: Distribution of Th1, Th2, Th0 and the Th1/Th2 cell ratios in human peripheral and endometrial T cells. Am J Reprod Immunol 1999;42:240–245.
Hennessy A, Pilmore HL, Simmons LA, Painter DM: A deficiency of placental IL-10 in preeclampsia. J Immunol 1999;163:3491–3495.
Arnold LL, Doherty TM, Flor AW, Simon JA, Chou JY, Chan WY, Mansfield BC: Pregnancy-specific glycoprotein gene expression in recurrent aborters: A potential correlation to IL-10 expression. Am J Reprod Immunol 1999;41:174–182.
Piccinni M-P, Maggi E, Romagnani S: Role of hormone-controlled T-cell cytokines in the maintenance of pregnancy. Biochem Soc Trans 2000;28:212–215.
Santhanam U, Avita C, Romero R, Vinguet H, Ida N, Sakuri S, Sehgal PB: Cytokines in normal and abnormal parturition: Elevated amniotic fluid interleukin-6 levels in women with premature rupture of membranes associated with intrauterine infection. Cytokine 1991;3:155–163.
Athayde N, Romero R, Maymon E, Gomez R, Pacora P, Yoon BH, Edwin SS: Interleukin-16 in pregnancy, parturition, rupture of fetal membranes and microbial invasion of the amniotic cavity. Am J Reprod Immunol 2000;182:135–141.
Denison FC, Kelly RW, Calder AA, Riley SC: Cytokine secretion by human fetal membranes, decidua and placenta at term. Hum Reprod 1998;13:3560–3565.
Lea RG, Riley SC, Antipatis C, Hannah L, Ashworth CJ, Clark DA, Critchley HOD: Cytokines and the regulation of apoptosis in reproductive tissues: A review. Am J Reprod Immunol 1999;42:100–109.
Tibbetts TA, DeMayo F, Rich S, Conneely OM, O’Malley BW: Progesterone receptors in the thymus are required for thymic involution during pregnancy and normal fertility. Proc Natl Acad Sci USA 1999;96:12021–12026.
Piccinni M-P, Giudizi M-G, Biagiotti R, Beloni L, Giannarini L, Sampognardo S, Parronchi P, Manetti R, Annunziato F, Livi C, Romagnani S, Maggi E: Progesterone favours the development of human T helper cells producing Th2-type cytokines and promotes both IL-4 production and membrane CD30 expression in established Th1 cell clones. J Immunol 1995;155:128–133.
Hamano N, Terada N, Maesako K, Hohki G, Ito T, Yamashita T, Konno A: Effect of female hormones on the production of IL-4 and IL-13 from peripheral blood mononuclear cells. Acta Otolaryngol 1998;537:27–31.
Faust Z, Laskarin G, Rukavina D, Szekeres-Bartho J: Progesterone-induced blocking factor inhibits degranulation of natural killer cells. Am J Reprod Immunol 1999;42:71–75.
Rachmilewitz J, Riley GJ, Tykocinski ML: Placental protein 14 functions as a direct T-cell inhibitor. Cell Immunol 1998;191:26–33.
Sharkey A, 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;53:955–962.
Saito S, Umekage H, Sakamoto Y, Sakai M, Tanebe K, Sasaki Y, Morikawa H: Increased T-helper-1-type immunity and decreased T-helper-2-type immunity in patients with preeclampsia. Am J Reprod Immunol 1999;41:297–306.
Uzumcu M, Coskun S, Jaroudi K, Hollanders JMG: Effect of human chorionic gonadotropin on cytokine production from human endometrial cell in vitro. Am J Reprod Immunol 1998;40:83–88.
Hunt JS, Miller L, Roby KF, Huang J, Platt JS, deBrot BL: Female steroid hormones regulate production of pro-inflammatory molecules in uterine leukocytes. J Reprod Immunol 1997;35:87–99.
Dealtry GB, Clark DE, Sharkey A, Charnock-Jones DS, Smith SK: Expression and localisation of the Th2-type cytokine IL-13 and its receptor in the placenta during human pregnancy. Am J Reprod Immunol 1998;40:283–290.
Hanna N, Hanna I, Hleb M, Wagner E, Dougherty J, Balkundi D, Padbury J, Sharma S: Gestational age-dependent expression of IL-10 and its receptor in human placental tissues and isolated cytotrophoblasts. J Immunol 2000;164:5721–5728.
Bennett WA, Lagoo-Deenadayalan S, Whitworth NS, Stopple JA, Barber WH, Hale E, Brackin MN, Cowan BD: First-trimester human chorionic villi express both immunoregulatory and inflammatory cytokines: A role for IL-10 in regulating the cytokine network of pregnancy. Am J Reprod Immunol 1999;41:70–78.
Vince GS, Johnson PM: Is there a Th2 bias in human pregnancy? J Reprod Immunol 1996;32:101–104.
Williams TJ, Jones CA, Miles EA, Warner JO, Warner JA: Fetal and neonatal IL-13 production during pregnancy and at birth and subsequent development of atopic symptoms. J Allergy Clin Immunol 1999;105:951–959.
Athayde N, Romero R, Maymon E, Gomez R, Pacora P, Araneda H, Yoon BH: A role for the novel cytokine RANTES in pregnancy and parturition. Am J Obstet Gynecol 1999;181:989–994.
Yoon BH, Romero R, Park JS, Kim SH, Choi JH, Han TR: Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years. Am J Obstet Gynecol 2000;182:675–681.
Veith GL, Rice GE: Interferon gamma expression during human pregnancy and in association with labor. Gynecol Obstet Invest 1999;48:163–167.
Lim KJH, Odukoya OA, Ajjan RA, Li TC, Weetman AP, Cooke ID: Profile of cytokine mRNA expression in peri-implantation human endometrium. Mol Hum Reprod 1998;4:77–81.
Searle RF, Bromage SJ, Palmer JE, Lang AK: Human amniotic fluid lacks interleukin-2 and interleukin-15 but can interact with the beta-chain of the interleukin-2 receptor. Immunology 2000;99:411–417.
Blumenstein M, Hansen WR, DeVal D, Mitchell MD: Differential regulation in human amnion epithelial and fibroblast cells of prostaglandin E-2 production and prostaglandin H synthase-2 mRNA expression by dexamethasone but not tumor necrosis factor-alpha. Placenta 2000;21:210–217.
Keelan JA, Marvin KW, Sato TA, Coleman M, McCowan LME, Mitchell MD: Cytokine abundance in placental tissues: Evidence of inflammatory activation in gestational membranes with term and preterm parturition. Am J Obstet Gynecol 1999;181:1530–1536.
Luo LH, Ibaragi T, Maeda M, Nozawa M, Kasahara T, Sakai Y, Tanebe K, Saito S: Interleukin-8 levels and granulocyte counts in cervical mucus during pregnancy. Am J Reprod Immunol 2000;43:78–84.
Maymon E, Ghezzi F, Edwin SS, Mazor M, Yoon BH, Gomez R, Romero R: The tumor necrosis factor alpha and its soluble receptor profile in term and preterm parturition. Am J Obstet Gynecol 1999;181:1142–1148.
Hunt JS, Rasmussen CA: The tumor necrosis factor gene family in pregnancy. Trophoblast Res 1998;11:139–147.
Steinborn A, Sohn C, Sayehli C, Baudendistel A, Huwelmeier D, Solbach C: Spontaneous labour at term is associated with fetal monocyte activation. Clin Exp Immunol 1999;117:147–152.
Sharkey A: Cytokines and embryo/endometrial interactions. Reprod Med Rev 1995;4:87.
Jones AC, Miles EA, Warner JO, Colwell BM, Bryant TN, Warner JA: Fetal peripheral blood mononuclear cell proliferative responses to mitogenic and allergenic stimuli during gestation. Pediatr Allergy Immunol 1996;7:109–116.
Kashlan F, Smulian J, Shen-Schwarz S, Anwar M, Hiatt M, Hegyi T: Umbilical vein interleukin 6 and tumor necrosis factor alpha plasma concentrations in the very preterm infant. Pediatr Infect Dis J 2000;19:238–243.
Malhotra I, Ouma J, Wamachi A, Kioko J, Mungai P, Omollo A, Elson L, Koech D, Kazura JW, King CL: In utero exposure to helminth and mycobacterial antigens generates cytokine responses similar to that observed in adults. J Clin Invest 1997;99:1759–1766.
Prescott SL, Macaubas C, Holt BJ, Smallacombe TB, Loh R, Sly PD, Holt PG: Transplacental priming of the human immune system to environmental allergens: Universal skewing of initial T cell responses toward the Th2 cytokine profile. J Immunol 1998;160:4730–4737.
Prescott SL, Macaubas C, Smallacombe T, Holt BJ, Sly PD, Holt PG: Development of allergen-specific T-cell memory in atopic and normal children. Lancet 1999;353:196–200.
Sakai K, Yokoyama A, Kohno N, Hiwada K: Effect of different sensitizing doses of antigen in a murine model of atopic asthma. Clin Exp Immunol 1999;118:9–15.
Adkins B, Du RQ: Newborn mice develop balanced Th1/Th2 primary effector responses in vivo but are biased to Th2 secondary responses. J Immunol 1998;160:4217–4224.
Warner JA: Primary sensitisation in infants. Ann Allergy Asthma Immunol 1999;83:426–430.
Adkins B: T-cell function in newborn mice and humans. Immunol Today 1999;20:330–335.
Zoumakis E, Margioris AN, Stournaras C, Dermitzaki E, Angelakis E, Makrigiannakis A, Koumantakis E, Gravanis A: Corticotrophin-releasing hormone (CRH) interacts with inflammatory prostaglandins and interleukins and affects the decidualisation of human endometrial stroma. Mol Hum Reprod 2000;6:344–351.
Dame JB, Juul SE: The distribution of receptors for the pro-inflammatory cytokines interleukin (IL)-6 and IL-8 in the developing human fetus. Early Hum Dev 2000;58:25–39.
de Moraes-Pinto MI, Vince GS, Flanagan BF, Hart CA, Johnson PJ: Localisation of IL-4 and IL-4 receptors in the human term placenta, decidua and amniochorionic membranes. Immunology 1997;90:87–94.
Bowen JA, Hunt JS: The role of integrins in reproduction. Proc Soc Exp Biol Med 2000;223:331–343.
Meissner A, Chardonnens D, Campana A, Bischof P: Effects of tumor necrosis factor-alpha, interleukin-1 alpha, macrophage colony stimulating factor and transforming growth factor beta on trophoblast matrix metalloproteinases. Mol Hum Repord 1999;5:252–260.
Meissner A, Cameo P, Islami D, Campana A, Bischof P: Effects of IL-6 on cytotrophoblastic cells. Mol Hum Reprod 1999;11:1055–1058.
Roth I, Fischer SJ: IL-10 is an autocrine inhibitor of human placental cytotrophoblast MMP-9 production and invasion. Dev Biol 1999;205:194–204.
Szony BJ, Bata-Csorgo Z, Bartfai G, Kemeny L, Dobozy A, Kovacs L: Interleukin-10 receptors are expressed by basement membrane anchored, alpha(6) integrin(+) cytotrophoblast cells in early human placenta. Mol Hum Reprod 1999;5:1059–1065.
Gorivodsky M, Zemlyak I, Orenstein H, Savion S, Fein A, Torchinsky A, Toder V: TNF-alpha messenger RNA and protein expression in the uteroplacental unit of mice with pregnancy loss. J Immunol 1998;160:4280–4288.
Phillips TA, Ni J, Pan GH, Ruben SM, Wei YF, Pace JL, Hunt JS: TRAIL (Apo-2L) and TRAIL receptors in human placentas: Implications for immune privilege. J Immunol 1999;162:6053–6059.
Hammer A, Dohr G: Apoptotic nuclei within the uterine decidua of first trimester pregnancy arise from CD45-positive leukocytes. Am J Reprod Immunol 1999;42:88–94.
Mitchell MD, Goodwin V, Mesnage S, Keelan JA: Cytokine-induced coordinate expression of enzymes of prostaglandin biosynthesis and metabolism: 15-hydroxyprostaglandin dehydrogenase. Prostaglandins Leukot Essent Fatty Acids 2000;62:1–5.
Brown NL, Alvi SA, Elder MG, Bennett PR, Sullivan MHF: The regulation of prostaglandin output from term intact fetal membranes by anti-inflammatory cytokines. Immunology 2000;99:124–133.
Rasmussen CA, Pace JL, Banerjee S, Phillips TA, Hunt JS: Trophoblastic cell lines generated from tumor necrosis factor receptor-deficient mice reveal specific functions for the two tumor necrosis factor receptors. Placenta 1999;20:213–222.
Okada S, Okada H, Sanezumi M, Nakajima T, Yasuda K, Kanzaki H: Expression of interleukin-15 in human endometrium and decidua. Mol Hum Reprod 2000;6:75–80.
Verma S, Hiby SE, Loke YW, King A: Human decidual natural killer cells express the receptor for and respond to the cytokine interleukin 15. Biol Reprod 2000;62:959–968.
Arima K, Nasu K, Narahara H, Fujisawa K, Matsui N, Miyakawa I: Effects of lipopolysaccharide and cytokines on production of RANTES by cultured human endometrial stromal cells. Mol Hum Reprod 2000;6:246–251.
Fernandez N, Cooper J, Sprinks M, AbdElrahman M, Fiszer D, Kurpisz M, Dealtry G: A critical review of the role of the major histocompatibility complex in fertilisation, preimplantantion development and feto-maternal interactions. Hum Reprod Update 1999;5:234–248.
McCracken SA, Layton JE, Shorter SC, Starkey PM, Barlow DH, Mardon HJ: Expression of granulocyte-colony stimulating factor and its receptor is regulated during the development of the human placenta. J Endocrinol 1996;149:249–258.
Stallmach T, Hebisch G, Joller-Jemelka HI, Orban P, Schwaller J, Engelmann M: Cytokine production and visualised effects in the feto-maternal unit. Lab Invest 1995;73:384.
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