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

Expert Review of Clinical Immunology

Volumn 7, Issue 5, 2011, Pages 603-609

  Markert, Udo R ^a   Morales Prieto, Diana M ^a   Fitzgerald, Justine S ^a  

^a JENA UNIVERSITY HOSPITAL   (Germany)

Author keywords

abortion; IL 11; IL 6; implantation; infertility; leukemia inhibitory factor; LIF; placenta; pregnancy; STAT; trophoblast

Indexed keywords

GAMMA INTERFERON; GELATINASE B; INTERLEUKIN 11; INTERLEUKIN 11 RECEPTOR ALPHA; INTERLEUKIN 6; INTERLEUKIN 6 RECEPTOR; JANUS KINASE; LEUKEMIA INHIBITORY FACTOR; MITOGEN ACTIVATED PROTEIN KINASE; RECOMBINANT CYTOKINE; RECOMBINANT HUMAN LEUKEMIA INHIBITORY FACTOR; STAT3 PROTEIN; UNCLASSIFIED DRUG;

ENZYME ACTIVATION; ENZYME ACTIVITY; FERTILIZATION; FETUS RESORPTION; GENE EXPRESSION; HUMAN; IMMUNE DYSREGULATION; NONHUMAN; PREGNANCY; PROTEIN EXPRESSION; REVIEW; SIGNAL TRANSDUCTION; TH17 CELL;

ANIMALS; FEMALE; FERTILITY; HUMANS; INTERLEUKIN-11; INTERLEUKIN-6; LEUKEMIA INHIBITORY FACTOR; PREGNANCY; PREGNANCY COMPLICATIONS;

EID: 80052628007     PISSN: 1744666X     EISSN: 17448409     Source Type: Journal    
DOI: 10.1586/eci.11.60     Document Type: Review

References (84)

1. Bauer S, Kerr BJ, Patterson PH. The neuropoietic cytokine family in development, plasticity, disease and injury. Nat. Rev. Neurosci. 8(3), 221-232 (2007). (Pubitemid 46294661)
2. 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).
3. 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 b. Fertil. Steril. 66(5), 741-747 (1996). (Pubitemid 26357574)
4. 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). (Pubitemid 36032847)
5. 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). (Pubitemid 39136805)
6. 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. Placenta 29(12), 1024-1028 (2008).
7. 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). (Pubitemid 30018038)
8. 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). (Pubitemid 30470094)
9. 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). (Pubitemid 38239744)
10. 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:10.3109/1476 7058.2011.575482 (2011) (Epub ahead of print).
11. 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). (Pubitemid 47382232)
12. Jasper MJ, Tremellen KP, Robertson SA. Reduced expression of IL-6 and IL-1a mRNAs in secretory phase endometrium of women with recurrent miscarriage. J. Reprod. Immunol. 73(1), 74-84 (2007). (Pubitemid 46161830)
13. 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).
14. 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).
15. + cells in women with reproductive failure. J. Reprod. Immunol. 82(2), 158-165 (2009).
16. Vitoratos N, Papadias C, Economou E, Makrakis E, Panoulis C, Creatsas G. Elevated circulating IL-1b and TNF-a, and unaltered IL-6 in first-trimester pregnancies complicated by threatened abortion with an adverse outcome. Med. Inflamm. 2006(4), 30485 (2006).
17. Takeda K, Noguchi K, Shi W et al. Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc. Natl Acad. Sci. USA 94(8), 3801-3804 (1997). (Pubitemid 27180453)
18. Poehlmann TG, Fitzgerald JS, Meissner A et al. Trophoblast invasion: tuning through LIF, signalling via STAT3. Placenta 26 (Suppl. A), S37-S41 (2005).
19. Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. J. Cell. Sci. 117(Pt 8), 1281-1283 (2004). (Pubitemid 38559804)
20. Decker T, Kovarik P. Serine phosphorylation of STATs. Oncogene 19(21), 2628-2637 (2000). (Pubitemid 30339219)
21. Maj T, Chelmonska-Soyta A. Pleiotropy and redundancy of STAT proteins in early pregnancy. Reprod. Domest. Anim. 42(4), 343-353 (2007). (Pubitemid 47041830)
22. 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).
23. 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. Update 14(4), 335-344 (2008). (Pubitemid 351858973)
24. 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). (Pubitemid 34569221)
25. 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). (Pubitemid 29518910)
26. 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).
27. Jovanovic M, Vicovac L. Interleukin-6 stimulates cell migration, invasion and integrin expression in HTR-8/SVneo cell line. Placenta 30(4), 320-328 (2009).
28. 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).
29. 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). (Pubitemid 28510710)
30. 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). (Pubitemid 27116689)
31. 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).
32. 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). (Pubitemid 24116388)
33. Keller DC, Du XX, Srour EF, Hoffman R, Williams DA. Interleukin-11 inhibits adipogenesis and stimulates myelopoiesis in human long-term marrow cultures. Blood 82(5), 1428-1435 (1993). (Pubitemid 23263958)
34. Tenney R, Stansfield K, Pekala PH. Interleukin 11 signaling in 3T3-L1 adipocytes. J. Cell Physiol. 202(1), 160-166 (2005). (Pubitemid 39603373)
35. 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).
36. Bilinski P, Roopenian D, Gossler A. Maternal IL-11Ra function is required for normal decidua and fetoplacental development in mice. Genes Dev. 12(14), 2234-2243 (1998). (Pubitemid 28348046)
37. 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). (Pubitemid 28144088)
38. Stewart CL, Kaspar P, Brunet LJ et al. Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor. Nature 359(6390), 76-79 (1992).
39. 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).
40. Dimitriadis E, Robb L, Liu YX et al. IL-11 and IL-11Ra immunolocalisation at primate implantation sites supports a role for IL-11 in placentation and fetal development. Reprod. Biol. Endocrinol. 1, 34 (2003).
41. Paiva P, Salamonsen LA, Manuelpillai U et al. Interleukin-11 promotes migration, but not proliferation, of human trophoblast cells, implying a role in placentation. Endocrinology 148(11), 5566-5572 (2007). (Pubitemid 350012659)
42. 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). (Pubitemid 32758837)
43. 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).
44. 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).
45. 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 Care 12(3), 212-219 (2007). (Pubitemid 47347160)
46. 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. USA 98(15), 8680-8685 (2001). (Pubitemid 32678087)
47. 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).
48. Lass A, Weiser W, Munafo A, Loumaye E. Leukemia inhibitory factor in human reproduction. Fertil. Steril. 76(6), 1091-1096 (2001). (Pubitemid 33116368)
49. Auernhammer CJ, Melmed S. Leukemia-inhibitory factor-neuroimmune modulator of endocrine function. Endocr. Rev. 21(3), 313-345 (2000). (Pubitemid 32275591)
50. Okahisa Y, Ujike H, Kunugi H et al. Leukemia inhibitory factor gene is associated with schizophrenia and working memory function. Prog. Neuropsychopharmacol. Biol. Psychiatry 34(1), 172-176 (2011).
51. 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). (Pubitemid 129495672)
52. 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).
53. 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 93(7), 3115-3120 (1996). (Pubitemid 26114373)
54. Stewart CL, Cullinan EB. Preimplantation development of the mammalian embryo and its regulation by growth factors. Dev. Genet. 21(1), 91-101 (1997). (Pubitemid 27381645)
55. Vogiagis D, Salamonsen LA. Review: the role of leukaemia inhibitory factor in the establishment of pregnancy. J. Endocrinol. 160(2), 181-190 (1999). (Pubitemid 29074687)
56. 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).
57. 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). (Pubitemid 27273551)
58. 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).
59. 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). (Pubitemid 27156457)
60. 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).
61. 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). (Pubitemid 24233801)
62. 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). (Pubitemid 41207401)
63. 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). (Pubitemid 29063877)
64. 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). (Pubitemid 34130289)
65. 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).
66. 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). (Pubitemid 28062285)
67. 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). (Pubitemid 28417333)
68. 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).
69. 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).
70. 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).
71. 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).
72. Aghajanova L. Update on the role of leukemia inhibitory factor in assisted reproduction. Curr. Opin. Obstet. Gynecol. 22(3), 213-219 (2010).
73. 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. Endocrinology 141(12), 4365-4372 (2000). (Pubitemid 32055110)
74. 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). (Pubitemid 43974973)
75. 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. Development 121(5), 1283-1299 (1995).
76. Sengupta J, Lalitkumar PG, Najwa AR, Ghosh D. Monoclonal anti-leukemia inhibitory factor antibody inhibits blastocyst implantation in the rhesus monkey. Contraception 74(5), 419-425 (2006). (Pubitemid 44527901)
77. 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. Reproduction 131(2), 341-349 (2006). (Pubitemid 43273693)
78. 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).
79. Knight D. Leukaemia inhibitory factor (LIF): a cytokine of emerging importance in chronic airway inflammation. Pulm. Pharmacol. Ther. 14(3), 169-176 (2001). (Pubitemid 32619921)
80. 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). (Pubitemid 37046923)
81. 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 ONE 6(5), e19665 (2011).
82. Dimitriadis E, Menkhorst E. New generation contraceptives: interleukin 11 family cytokines as non-steroidal contraceptive targets. J. Reprod. Immunol. 88(2), 233-239 (2011).
83. 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. USA 102(24), 8585-8590 (2005). (Pubitemid 40862779)
84. Koehn S, Schaefer HW, Ludwig M et al. Cell-specific RNA interference by peptide-inhibited-peptidase-activated siRNAs. J. RNAi Gene Silencing 6(2), 422-430 (2011).