Understanding the link between the IL-6 cytokine family and pregnancy: implications for future therapeutics

References

• Bauer S, Kerr BJ, Patterson PH. The neuropoietic cytokine family in development, plasticity, disease and injury. Nat. Rev. Neurosci.8(3), 221–232 (2007).
   PubMed Web of Science ®Google Scholar
• Tabibzadeh S, Kong QF, Babaknia A, May LT. Progressive rise in the expression of interleukin-6 in human endometrium during menstrual cycle is initiated during the implantation window. Hum. Reprod.10(10), 2793–2799 (1995).
   PubMed Web of Science ®Google Scholar
• Vandermolen DT, Gu Y. Human endometrial interleukin-6 (IL-6): in vivo messenger ribonucleic acid expression, in vitro protein production, and stimulation thereof by IL-1 β. Fertil. Steril.66(5), 741–747 (1996).
   PubMedGoogle Scholar
• Von Wolff M, Stieger S, Lumpp K, Bucking J, Strowitzki T, Thaler CJ. Endometrial interleukin-6 in vitro is not regulated directly by female steroid hormones, but by pro-inflammatory cytokines and hypoxia. Mol. Hum. Reprod.8(12), 1096–1102 (2002).
   PubMedGoogle Scholar
• Classen-Linke I, Muller-Newen G, Heinrich PC, Beier HM, Von Rango U. The cytokine receptor gp130 and its soluble form are under hormonal control in human endometrium and decidua. Mol. Hum. Reprod.10(7), 495–504 (2004).
   PubMedGoogle Scholar
• Zhao S, Gu Y, Dong Q, Fan R, Wang Y. Altered interleukin-6 receptor, IL-6R and gp130, production and expression and decreased SOCS-3 expression in placentas from women with pre-eclampsia. Placenta29(12), 1024–1028 (2008).
   PubMed Web of Science ®Google Scholar
• Lim KJ, Odukoya OA, Ajjan RA, Li TC, Weetman AP, Cooke ID. The role of T-helper cytokines in human reproduction. Fertil. Steril.73(1), 136–142 (2000).
   PubMed Web of Science ®Google Scholar
• Von Wolff M, Thaler CJ, Strowitzki T, Broome J, Stolz W, Tabibzadeh S. Regulated expression of cytokines in human endometrium throughout the menstrual cycle: dysregulation in habitual abortion. Mol. Hum. Reprod.6(7), 627–634 (2000).
   PubMed Web of Science ®Google Scholar
• Gutierrez G, Sarto A, Berod L et al. Regulation of interleukin-6 fetoplacental levels could be involved in the protective effect of low-molecular weight heparin treatment on murine spontaneous abortion. Am. J. Reprod. Immunol.51(2), 160–165 (2004).
   PubMedGoogle Scholar
• Galazios G, Tsoulou S, Zografou C et al. The role of cytokines IL-6 and IL-8 in the pathogenesis of spontaneous abortions. J. Matern. Fetal. Neona. DOI:10.3109/14767058.2011.575482 (2011) (Epub ahead of print).
   Google Scholar
• Hattori Y, Nakanishi T, Ozaki Y, Nozawa K, Sato T, Sugiura-Ogasawara M. Uterine cervical inflammatory cytokines, interleukin-6 and -8, as predictors of miscarriage in recurrent cases. Am. J. Reprod. Immunol.58(4), 350–357 (2007).
   PubMed Web of Science ®Google Scholar
• Jasper MJ, Tremellen KP, Robertson SA. Reduced expression of IL-6 and IL-1α mRNAs in secretory phase endometrium of women with recurrent miscarriage. J. Reprod. Immunol.73(1), 74–84 (2007).
   PubMed Web of Science ®Google Scholar
• Robertson SA, O’Connell A, Ramsey A. The effect of interleukin-6 deficiency on implantation, fetal development and parturition in mice. Proc. Aust. Soc. Reprod. Biol.31, 97 (2000).
   Google Scholar
• Junovich G, Dubinsky V, Gentile T, Sarto A, Pasqualini S, Gutierrez G. Comparative immunological effect of anticoagulant and antioxidant therapy in the prevention of abortion in mice. Am. J. Reprod. Immunol.65(2), 104–109 (2011).
   PubMedGoogle Scholar
• Arruvito L, Billordo A, Capucchio M, Prada ME, Fainboim L. IL-6 trans-signaling and the frequency of CD4+FOXP3+ cells in women with reproductive failure. J. Reprod. Immunol.82(2), 158–165 (2009).
   PubMedGoogle Scholar
• Vitoratos N, Papadias C, Economou E, Makrakis E, Panoulis C, Creatsas G. Elevated circulating IL-1β and TNF-α, and unaltered IL-6 in first-trimester pregnancies complicated by threatened abortion with an adverse outcome. Med. Inflamm.2006(4), 30485 (2006).
   PubMedGoogle Scholar
• Takeda K, Noguchi K, Shi W et al. Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc. Natl Acad. Sci. USA94(8), 3801–3804 (1997).
   PubMed Web of Science ®Google Scholar
• Poehlmann TG, Fitzgerald JS, Meissner A et al. Trophoblast invasion: tuning through LIF, signalling via STAT3. Placenta26(Suppl. A), S37–S41 (2005).
   PubMed Web of Science ®Google Scholar
• Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. J. Cell. Sci.117(Pt 8), 1281–1283 (2004).
   PubMed Web of Science ®Google Scholar
• Decker T, Kovarik P. Serine phosphorylation of STATs. Oncogene19(21), 2628–2637 (2000).
   PubMed Web of Science ®Google Scholar
• Maj T, Chelmonska-Soyta A. Pleiotropy and redundancy of STAT proteins in early pregnancy. Reprod. Domest. Anim.42(4), 343–353 (2007).
   PubMedGoogle Scholar
• Jones HN, Jansson T, Powell TL. IL-6 stimulates system A amino acid transporter activity in trophoblast cells through STAT3 and increased expression of SNAT2. Am. J. Physiol. Cell Physiol.297(5), C1228–C1235 (2009).
   PubMed Web of Science ®Google Scholar
• Fitzgerald JS, Poehlmann TG, Schleussner E, Markert UR. Trophoblast invasion: the role of intracellular cytokine signalling via signal transducer and activator of transcription 3 (STAT3). Hum. Reprod. Update14(4), 335–344 (2008).
   PubMed Web of Science ®Google Scholar
• Das C, Kumar VS, Gupta S, Kumar S. Network of cytokines, integrins and hormones in human trophoblast cells. J. Reprod. Immunol.53(1–2), 257–268 (2002).
   PubMed Web of Science ®Google Scholar
• Meisser A, Cameo P, Islami D, Campana A, Bischof P. Effects of interleukin-6 (IL-6) on cytotrophoblastic cells. Mol. Hum. Reprod.5(11), 1055–1058 (1999).
   PubMed Web of Science ®Google Scholar
• Dubinsky V, Poehlmann TG, Suman P, Gentile T, Markert UR, Gutierrez G. Role of regulatory and angiogenic cytokines in invasion of trophoblastic cells. Am. J. Reprod. Immunol.63(3), 193–199 (2010).
   PubMed Web of Science ®Google Scholar
• Jovanovic M, Vicovac L. Interleukin-6 stimulates cell migration, invasion and integrin expression in HTR-8/SVneo cell line. Placenta30(4), 320–328 (2009).
   PubMed Web of Science ®Google Scholar
• Huang C, Yang G, Jiang T, Huang K, Cao J, Qiu Z. Effects of IL-6 and AG490 on regulation of STAT3 signaling pathway and invasion of human pancreatic cancer cells in vitro. J. Exp. Clin. Cancer Res.29, 51 (2010).
   PubMed Web of Science ®Google Scholar
• Nishino H, Miyata M, Kitamura K. The effect of interleukin-6 on enhancing the invasiveness of head and neck cancer cells in vitro. Eur. Arch. Otorhinolaryngol.255(9), 468–472 (1998).
   PubMedGoogle Scholar
• Obata NH, Tamakoshi K, Shibata K, Kikkawa F, Tomoda Y. Effects of interleukin-6 on in vitro cell attachment, migration and invasion of human ovarian carcinoma. Anticancer Res.17(1A), 337–342 (1997).
   PubMed Web of Science ®Google Scholar
• Ravishankaran P, Karunanithi R. Clinical significance of preoperative serum interleukin-6 and C-reactive protein level in breast cancer patients. World J. Surg. Oncol.9(1), 18 (2011).
   PubMed Web of Science ®Google Scholar
• Girasole G, Passeri G, Jilka RL, Manolagas SC. Interleukin-11: a new cytokine critical for osteoclast development. J. Clin. Invest.93(4), 1516–1524 (1994).
   PubMed Web of Science ®Google Scholar
• Keller DC, Du XX, Srour EF, Hoffman R, Williams DA. Interleukin-11 inhibits adipogenesis and stimulates myelopoiesis in human long-term marrow cultures. Blood82(5), 1428–1435 (1993).
   PubMed Web of Science ®Google Scholar
• Tenney R, Stansfield K, Pekala PH. Interleukin 11 signaling in 3T3-L1 adipocytes. J. Cell Physiol.202(1), 160–166 (2005).
   PubMed Web of Science ®Google Scholar
• Paiva P, Menkhorst E, Salamonsen L, Dimitriadis E. Leukemia inhibitory factor and interleukin-11: critical regulators in the establishment of pregnancy. Cytokine & Growth Factor Rev.20(4), 319–328 (2009).
   PubMed Web of Science ®Google Scholar
• Bilinski P, Roopenian D, Gossler A. Maternal IL-11Rα function is required for normal decidua and fetoplacental development in mice. Genes Dev.12(14), 2234–2243 (1998).
   PubMedGoogle Scholar
• 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.4(3), 303–308 (1998).
   PubMed Web of Science ®Google Scholar
• Stewart CL, Kaspar P, Brunet LJ et al. Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor. Nature359(6390), 76–79 (1992).
   PubMed Web of Science ®Google Scholar
• Chen HF, Lin CY, Chao KH, Wu MY, Yang YS, Ho HN. Defective production of interleukin-11 by decidua and chorionic villi in human anembryonic pregnancy. J. Clin. Endocrinol. Metab.87(5), 2320–2328 (2002).
   PubMed Web of Science ®Google Scholar
• Dimitriadis E, Robb L, Liu YX et al. IL-11 and IL-11Rα immunolocalisation at primate implantation sites supports a role for IL-11 in placentation and fetal development. Reprod. Biol. Endocrinol.1, 34 (2003).
   PubMedGoogle Scholar
• Paiva P, Salamonsen LA, Manuelpillai U et al. Interleukin-11 promotes migration, but not proliferation, of human trophoblast cells, implying a role in placentation. Endocrinology148(11), 5566–5572 (2007).
   PubMedGoogle Scholar
• Koumantaki Y, Matalliotakis I, Sifakis S et al. Detection of interleukin-6, interleukin-8, and interleukin-11 in plasma from women with spontaneous abortion. Eur. J. Obstet. Gynecol. Reprod. Biol.98(1), 66–71 (2001).
   PubMedGoogle Scholar
• Suman P, Poehlmann TG, Prakash GJ, Markert UR, Gupta SK. Interleukin-11 increases invasiveness of JEG-3 choriocarcinoma cells by modulating STAT3 expression. J. Reprod. Immunol.82(1), 1–11 (2009).
   PubMedGoogle Scholar
• Paiva P, Salamonsen LA, Manuelpillai U, Dimitriadis E. Interleukin 11 inhibits human trophoblast invasion indicating a likely role in the decidual restraint of trophoblast invasion during placentation. Biol. Reprod.80(2), 302–310 (2009).
   PubMedGoogle Scholar
• Guney M, Oral B, Karahan N, Mungan T. Expression of leukaemia inhibitory factor (LIF) during the window of implantation in copper T380A intrauterine device users. Eur. J. Contracept. Reprod. Health Care12(3), 212–219 (2007).
   PubMed Web of Science ®Google Scholar
• Cheng JG, Chen JR, Hernandez L, Alvord WG, Stewart CL. Dual control of LIF expression and LIF receptor function regulate STAT3 activation at the onset of uterine receptivity and embryo implantation. Proc. Natl Acad. Sci. USA98(15), 8680–8685 (2001).
   PubMed Web of Science ®Google Scholar
• Gearing DP, Gough NM, King JA et al. Molecular cloning and expression of cDNA encoding a murine myeloid leukaemia inhibitory factor (LIF). EMBO J.6(13), 3995–4002 (1987).
   PubMed Web of Science ®Google Scholar
• Lass A, Weiser W, Munafo A, Loumaye E. Leukemia inhibitory factor in human reproduction. Fertil. Steril.76(6), 1091–1096 (2001).
   PubMed Web of Science ®Google Scholar
• Auernhammer CJ, Melmed S. Leukemia-inhibitory factor-neuroimmune modulator of endocrine function. Endocr. Rev.21(3), 313–345 (2000).
   PubMed Web of Science ®Google Scholar
• Okahisa Y, Ujike H, Kunugi H et al. Leukemia inhibitory factor gene is associated with schizophrenia and working memory function. Prog. Neuropsychopharmacol. Biol. Psychiatry34(1), 172–176 (2011).
   Google Scholar
• Knight DA, Lydell CP, Zhou D, Weir TD, Robert Schellenberg R, Bai TR. Leukemia inhibitory factor (LIF) and LIF receptor in human lung. Distribution and regulation of LIF release. Am. J. Respir. Cell Mol. Biol.20(4), 834–841 (1999).
   PubMed Web of Science ®Google Scholar
• Sawai K, Matsuzaki N, Kameda T et al. Leukemia inhibitory factor produced at the fetomaternal interface stimulates chorionic gonadotropin production: its possible implication during pregnancy, including implantation period. J. Clin. Endocrinol. Metab.80(4), 1449–1456 (1995).
   PubMed Web of Science ®Google Scholar
• 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. USA93(7), 3115–3120 (1996).
   PubMed Web of Science ®Google Scholar
• Stewart CL, Cullinan EB. Preimplantation development of the mammalian embryo and its regulation by growth factors. Dev. Genet.21(1), 91–101 (1997).
   PubMedGoogle Scholar
• Vogiagis D, Salamonsen LA. Review: the role of leukaemia inhibitory factor in the establishment of pregnancy. J. Endocrinol.160(2), 181–190 (1999).
   PubMedGoogle Scholar
• Fraccaroli L, Grasso E, Zeitler E et al. Modulation of maternal LIF producers T cells by trophoblast and paternal antigens. Am. J. Reprod. Immunol.65(2), 133–145 (2011).
   PubMedGoogle Scholar
• Arici A, Oral E, Bahtiyar O, Engin O, Seli E, Jones EE. Leukaemia inhibitory factor expression in human follicular fluid and ovarian cells. Hum. Reprod.12(6), 1233–1239 (1997).
   PubMedGoogle Scholar
• Harvey MB, Leco KJ, Arcellana-Panlilio MY, Zhang X, Edwards DR, Schultz GA. Roles of growth factors during peri-implantation development. Hum. Reprod.10(3), 712–718 (1995).
   PubMedGoogle Scholar
• Laird SM, Tuckerman EM, Dalton CF, Dunphy BC, Li TC, Zhang X. The production of leukaemia inhibitory factor by human endometrium: presence in uterine flushings and production by cells in culture. Hum. Reprod.12(3), 569–574 (1997).
   PubMedGoogle Scholar
• Kojima K, Kanzaki H, Iwai M et al. Expression of leukaemia inhibitory factor (LIF) receptor in human placenta: a possible role for LIF in the growth and differentiation of trophoblasts. Hum. Reprod.10(7), 1907–1911 (1995).
   PubMedGoogle Scholar
• 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.101(2), 421–426 (1994).
   PubMedGoogle Scholar
• Fitzgerald JS, Tsareva SA, Poehlmann TG et al. Leukemia inhibitory factor triggers activation of signal transducer and activator of transcription 3, proliferation, invasiveness, and altered protease expression in choriocarcinoma cells. Int. J. Biochem. Cell Biol.37(11), 2284–2296 (2005).
   PubMed Web of Science ®Google Scholar
• Sharkey AM, King A, Clark DE et al. Localization of leukemia inhibitory factor and its receptor in human placenta throughout pregnancy. Biol. Reprod.60(2), 355–364 (1999).
   PubMedGoogle Scholar
• Ledee-Bataille N, Lapree-Delage G, Taupin JL, Dubanchet S, Frydman R, Chaouat G. Concentration of leukaemia inhibitory factor (LIF) in uterine flushing fluid is highly predictive of embryo implantation. Hum. Reprod.17(1), 213–218 (2002).
   PubMed Web of Science ®Google Scholar
• Delage G, Moreau JF, Taupin JL et al.In-vitro endometrial secretion of human interleukin for DA cells/leukaemia inhibitory factor by explant cultures from fertile and infertile women. Hum. Reprod.10(9), 2483–2488 (1995).
   PubMed Web of Science ®Google Scholar
• Hambartsoumian E. Endometrial leukemia inhibitory factor (LIF) as a possible cause of unexplained infertility and multiple failures of implantation. Am. J. Reprod. Immunol.39(2), 137–143 (1998).
   PubMedGoogle Scholar
• Piccinni MP, Beloni L, Livi C, Maggi E, Scarselli G, Romagnani S. Defective production of both leukemia inhibitory factor and type 2 T-helper cytokines by decidual T cells in unexplained recurrent abortions. Nat. Med.4(9), 1020–1024 (1998).
   PubMed Web of Science ®Google Scholar
• Serafini PC, Silva ID, Smith GD, Motta EL, Rocha AM, Baracat EC. Endometrial claudin-4 and leukemia inhibitory factor are associated with assisted reproduction outcome. Reprod. Biol. Endocrinol.7, 30 (2009).
   PubMedGoogle Scholar
• Novotny Z, Krizan J, Sima R et al. Leukaemia inhibitory factor (LIF) gene mutations in women diagnosed with unexplained infertility and endometriosis have a negative impact on the IVF outcome. A pilot study. Folia. Biol. (Praha)55(3), 92–97 (2009).
   PubMed Web of Science ®Google Scholar
• Brinsden PR, Alam V, De Moustier B, Engrand P. Recombinant human leukemia inhibitory factor does not improve implantation and pregnancy outcomes after assisted reproductive techniques in women with recurrent unexplained implantation failure. Fertil. Steril.91(Suppl. 4), 1445–1447 (2009).
   PubMed Web of Science ®Google Scholar
• Fitzgerald JS, Toth B, Jeschke U, Schleussner E, Markert UR. Knocking off the suppressors of cytokine signaling (SOCS): their roles in mammalian pregnancy. J. Reprod. Immunol.83(1–2), 117–123 (2009).
   PubMed Web of Science ®Google Scholar
• Aghajanova L. Update on the role of leukemia inhibitory factor in assisted reproduction. Curr. Opin. Obstet. Gynecol.22(3), 213–219 (2010).
   PubMed Web of Science ®Google Scholar
• Chen JR, Cheng JG, Shatzer T, Sewell L, Hernandez L, Stewart CL. Leukemia inhibitory factor can substitute for nidatory estrogen and is essential to inducing a receptive uterus for implantation but is not essential for subsequent embryogenesis. Endocrinology141(12), 4365–4372 (2000).
   PubMed Web of Science ®Google Scholar
• Makrigiannakis A, Minas V, Kalantaridou SN, Nikas G, Chrousos GP. Hormonal and cytokine regulation of early implantation. Trends Endocrinol. Metab.17(5), 178–185 (2006).
   PubMed Web of Science ®Google Scholar
• Ware CB, Horowitz MC, Renshaw BR et al. Targeted disruption of the low-affinity leukemia inhibitory factor receptor gene causes placental, skeletal, neural and metabolic defects and results in perinatal death. Development121(5), 1283–1299 (1995).
   PubMed Web of Science ®Google Scholar
• Sengupta J, Lalitkumar PG, Najwa AR, Ghosh D. Monoclonal anti-leukemia inhibitory factor antibody inhibits blastocyst implantation in the rhesus monkey. Contraception74(5), 419–425 (2006).
   PubMedGoogle Scholar
• Song H, Lim H. Evidence for heterodimeric association of leukemia inhibitory factor (LIF) receptor and gp130 in the mouse uterus for LIF signaling during blastocyst implantation. Reproduction131(2), 341–349 (2006).
   PubMed Web of Science ®Google Scholar
• Schuringa JJ, Van Der Schaaf S, Vellenga E, Eggen BJ, Kruijer W. LIF-induced STAT3 signaling in murine versus human embryonal carcinoma (EC) cells. Exp. Cell Res.274(1), 119–129 (2002).
   PubMedGoogle Scholar
• Knight D. Leukaemia inhibitory factor (LIF): a cytokine of emerging importance in chronic airway inflammation. Pulm. Pharmacol. Ther.14(3), 169–176 (2001).
   PubMedGoogle Scholar
• Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem. J.374(Pt 1), 1–20 (2003).
   PubMed Web of Science ®Google Scholar
• Menkhorst E, Zhang JG, Sims NA et al. Vaginally administered PEGylated LIF antagonist blocked embryo implantation and eliminated non-target effects on bone in mice. PLoS ONE6(5), e19665 (2011).
   Google Scholar
• Dimitriadis E, Menkhorst E. New generation contraceptives: interleukin 11 family cytokines as non-steroidal contraceptive targets. J. Reprod. Immunol.88(2), 233–239 (2011).
   PubMed Web of Science ®Google Scholar
• Catalano RD, Johnson MH, Campbell EA, Charnock-Jones DS, Smith SK, Sharkey AM. Inhibition of STAT3 activation in the endometrium prevents implantation: a nonsteroidal approach to contraception. Proc. Natl Acad. Sci. USA102(24), 8585–8590 (2005).
   PubMed Web of Science ®Google Scholar
• Koehn S, Schaefer HW, Ludwig M et al. Cell-specific RNA interference by peptide-inhibited-peptidase-activated siRNAs. J. RNAi Gene Silencing6(2), 422–430 (2011).
   Google Scholar