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Inflammation and Pregnancy

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Abstract

Inflammation is a process by which tissues respond to various insults. It is characterized by upregulation of chemokines, cytokines, and pattern recognition receptors that sense microbes and tissue breakdown products. During pregnancy, the balance of Th1 (cell-mediated immunity) and Th2 (humoral immunity) cytokines is characterized by an initial prevalence of Th2 cytokines, followed by a progressive shift toward Th1 predominance late in gestation, that when is abnormal, may initiate and intensify the cascade of inflammatory cytokine production involved in adverse pregnancy outcomes. Maternal and placental hormones may affect the inflammatory pathway. Hypoxia and the innate immune response are 2 adaptive mechanisms by which organisms respond to perturbation in organ function, playing a major role in spontaneous abortion, intrauterine growth restriction, preeclampsia, and preterm delivery. The interaction between tissue remodeling factors, like matrix metalloproteinases, and vasoactive/hemostatic factors, like prostaglandin and coagulation factors, mediates this adaptive response.

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References

  1. Romero R, Espinoza J, Gonçalves LF, Kusanovic JP, Friel LA, Nien JK. Inflammation in preterm and term labour and delivery. Semin Fetal Neonatal Med. 2006;11:317–326.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Orsi NM, Tribe RM. Cytokine networks and the regulation of uterine function in pregnancy and parturition. J Neuroendocrinol. 2008;20:462–469.

    Article  CAS  PubMed  Google Scholar 

  3. Chaouat G. Regulation of T-cell activities at the fetoplacental interface—by placenta? Am J Reprod Immunol. 1999;42:199–204.

    Article  CAS  PubMed  Google Scholar 

  4. Zakar T, Hertelendy F. Progesterone withdrawal: key to parturition. Am J Obstet Gynecol. 2007;196:289–296.

    Article  CAS  PubMed  Google Scholar 

  5. Moriyama I, Sugawa T. Progesterone facilitates implantation of xenogenic cultured cells in hamster uterus. Nat New Biol. 1972;236:150–152.

    Article  CAS  PubMed  Google Scholar 

  6. Szekeres-Bartho J, Wilczynski JR, Basta P, Kalinka J. Role of progesterone and progestin therapy in threatened abortion and preterm labour. Front Biosci. 2008;13:1981–1990.

    Article  CAS  PubMed  Google Scholar 

  7. Elovitz MA, Mrinalini C. Can medroxyprogesterone acetate alter Toll-like receptor expression in a mouse model of intrauterine inflammation? Am J Obstet Gynecol. 2005;193(3 pt 2): 1149–1155.

    Article  CAS  PubMed  Google Scholar 

  8. Oner C, Schatz F, Kizilay G, et al. Progestin-inflammatory cytokine interactions affect matrix metalloproteinase-1 and -3 expression in term decidual cells: implications for treatment of chorioamnionitis-induced preterm delivery. J Clin Endocrinol Metab. 2008;93:252–259.

    Article  CAS  PubMed  Google Scholar 

  9. Allport VC, Pieber D, Slater DM, Newton R, White JO, Bennett PR. Human labour is associated with nuclear factor-kappaB activity which mediates cyclo-oxygenase-2 expression and is involved with the ‘functional progesterone withdrawal.’ Mol Hum Reprod. 2001;7:581–586.

    Article  CAS  Google Scholar 

  10. Bryant-Greenwood GD, Kern A, Yamamoto SY, Sadowsky DW, Novy MJ. Relaxin and the human fetal membranes. Reprod Sci. 2007;14(suppl 8):42–45.

    Article  CAS  PubMed  Google Scholar 

  11. Straub RH. The complex role of estrogens in inflammation. Endocr Rev. 2007;28:521–574.

    Article  CAS  PubMed  Google Scholar 

  12. Salem ML. Estrogen, a double-edged sword: modulation of TH1- and TH2-mediated inflammations by differential regulation of TH1/TH2 cytokine production. Curr Drug Targets Inflamm Allergy. 2004;3:97–104.

    Article  CAS  PubMed  Google Scholar 

  13. Luisi S, Florio P, Reis FM, Petraglia F. Expression and secretion of activin A: possible physiological and clinical implications. Eur J Endocrinol. 2001;145:225–236.

    Article  CAS  PubMed  Google Scholar 

  14. Petraglia F, Sacerdote P, Cossarizza A, et al. Inhibin and activin modulate human monocyte chemotaxis and human lymphocyte interferon-gamma production. J Clin Endocrinol Metab. 1991;72:496–502.

    Article  CAS  PubMed  Google Scholar 

  15. Ogawa K, Funaba M, Mathews LS, Mizutani T. Activin A stimulates type IV collagenase (matrix metalloproteinase-2) production in mouse peritoneal macrophages. J Immunol. 2000;165:2997–3003.

    Article  CAS  PubMed  Google Scholar 

  16. Funaba M, Ikeda T, Ogawa K, Murakami M, Abe M. Role of activin A in murine mast cells: modulation of cell growth, differentiation, and migration. J Leukoc Biol. 2003;73:793–801.

    Article  CAS  PubMed  Google Scholar 

  17. Shao L, Frigon NL Jr, Sehy DW, et al. Regulation of production of activin A in human marrow stromal cells and monocytes. Exp Hematol. 1992;20:1235–1242.

    CAS  PubMed  Google Scholar 

  18. Hübner G, Werner S. Serum growth factors and proinflammatory cytokines are potent inducers of activin expression in cultured fibroblasts and keratinocytes. Exp Cell Res. 1996;228:106–113.

    Article  CAS  PubMed  Google Scholar 

  19. Shao LE, Frigon Jr NL, Yu A, Palyash J, Yu J. Contrasting effects of inflammatory cytokines and glucocorticoids on the production of activin A in human marrow stromal cells and their implications. Cytokine. 1998;10:227–235.

    Article  CAS  PubMed  Google Scholar 

  20. Russell CE, Hedger MP, Brauman JN, de Kretser DM, Phillips DJ. Activin A regulates growth and acute phase proteins in the human liver cell line, HepG2. Mol Cell Endocrinol. 1999;148:129–136.

    Article  CAS  PubMed  Google Scholar 

  21. Werner S, Alzheimer C. Roles of activin in tissue repair, fibrosis, and inflammatory disease. Cytokine Growth Factor Rev. 2006;17:157–171.

    Article  CAS  PubMed  Google Scholar 

  22. Petersson M, Wiberg U, Lundeberg T, Uvnäs-Moberg K. Oxytocin decreases carrageenan induced inflammation in rats. Peptides. 2001;22:1479–1484.

    Article  CAS  PubMed  Google Scholar 

  23. Terzidou V, Lee Y, Lindström T, Johnson M, Thornton S, Bennett PR. Regulation of the human oxytocin receptor by nuclear factor-kappaB and CCAAT/enhancer-binding protein-beta. J Clin Endocrinol Metab. 2006;91:2317–2326.

    Article  CAS  PubMed  Google Scholar 

  24. Suda T, Kageyama K, Sakihara S, Nigawara T. Physiological roles of urocortins, human homologues of fish urotensin I, and their receptors. Peptides. 2004;25:1689–1701.

    Article  CAS  PubMed  Google Scholar 

  25. Agelaki S, Tsatsanis C, Gravanis A, Margioris AN. Corticotropin-releasing hormone augments proinflammatory cytokine production from macrophages in vitro and in lipopolysaccharide-induced endotoxin shock in mice. Infect Immun, 2002;70:6068–6074.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gonzalez-Rey E, Chorny A, Varela N, O’Valle F, Delgado M. Therapeutic effect of urocortin on collagen-induced arthritis by down-regulation of inflammatory and Th1 responses and induction of regulatory T cells. Arthritis Rheum. 2007;56:531–543.

    Article  CAS  PubMed  Google Scholar 

  27. Vaughan J, Donaldson C, Bittencourt J, et al. Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature. 1995;378:287–292.

    Article  CAS  PubMed  Google Scholar 

  28. Gravanis A, Margioris AN. The corticotropin-releasing factor (CRF) family of neuropeptides in inflammation: potential therapeutic applications. Curr Med Chem. 2005;12:1503–1512.

    Article  CAS  PubMed  Google Scholar 

  29. Tsatsanis C, Androulidaki A, Dermitzaki E, et al. Urocortin 1 and Urocortin 2 induce macrophage apoptosis via CRFR2. FEBS Lett. 2005;579:4259–4264.

    Article  CAS  PubMed  Google Scholar 

  30. Agnello D, Bertini R, Sacco S, Meazza C, Villa P, Ghezzi P. Corticosteroid-independent inhibition of tumor necrosis factor production by the neuropeptide urocortin. Am J Physiol Endocrinol Metab. 1998;275:E757-E762.

    Article  CAS  Google Scholar 

  31. Delgado M, Ganea D. Anti-inflammatory neuropeptides: a new class of endogenous immunoregulatory agents. Brain Behav Immun. 2008 Jun 14. (Epub ahead of print).

  32. Elovitz MA, Wang Z, Chien EK, Rychlik DF, Phillippe M. A new model for inflammation-induced preterm birth: the role of platelet-activating factor and Toll-like receptor-4. Am J Pathol. 2003;163:2103–2111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lorenz E, Hallman M, Marttila R, Haataja R, Schwartz DA. Association between the Asp299Gly polymorphisms in the Toll-like receptor 4 and premature births in the Finnish population. Pediatr Res. 2002;52:373–376.

    Article  CAS  PubMed  Google Scholar 

  34. Krediet TG, Wiertsema SP, Vossers MJ, et al. Toll-like receptor 2 polymorphism is associated with preterm birth. Pediatr Res. 2007;62:474–476.

    Article  CAS  PubMed  Google Scholar 

  35. Okamura Y, Watari M, Jerud ES, et al. The extra domain A of fibronectin activates Toll-like receptor 4. J Biol Chem. 2001;276:10229–10233.

    Article  CAS  PubMed  Google Scholar 

  36. Taylor KR, Yamasaki K, Radek KA, et al. Recognition of hyaluronan released in sterile injury involves a unique receptor complex dependent on Toll-like receptor 4, CD44, and MD-2. J Biol Chem. 2007;282:18265–18275.

    Article  CAS  PubMed  Google Scholar 

  37. Schaefer L, Babelova A, Kiss E, et al. The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages. J Clin Invest. 2005;115: 2223–2233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Tsung A, Klune JR, Zhang X, et al. HMGB1 release induced by liver ischemia involves Toll-like receptor 4 dependent reactive oxygen species production and calcium-mediated signaling. J Exp Med. 2007;204:2913–2923.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kawai T, Akira S. Signaling to NF-kappaB by Toll-like receptors. Trends Mol Med. 2007;13:460–469.

    Article  CAS  PubMed  Google Scholar 

  40. Orsi NM, Gopichandran N, Simpson NA. Genetics of pre-term labour. Best Pract Res Clin Obstet Gynaecol. 2007;21: 757–772.

    Article  PubMed  Google Scholar 

  41. Macones GA, Parry S, Elkousy M, Clothier B, Ural SH, Strauss JF 3rd. A polymorphism in the promoter region of TNF and bacterial vaginosis: preliminary evidence of gene-environment interaction in the etiology of spontaneous pre-term birth. Am J Obstet Gynecol. 2004;190:1504–1508.

    Article  CAS  PubMed  Google Scholar 

  42. Wang H, Parry S, Macones G, et al. Functionally significant SNP MMP8 promoter haplotypes and preterm premature rupture of membranes (PPROM). Hum Mol Genet. 2004;13:2659–2669.

    Article  CAS  PubMed  Google Scholar 

  43. Li Z, Zhang Y, Ying Ma J, et al. Recombinant vascular endothelial growth factor 121 attenuates hypertension and improves kidney damage in a rat model of preeclampsia. Hypertension. 2007;50:686–692.

    Article  CAS  PubMed  Google Scholar 

  44. Levine RJ, Maynard SE, Qian C, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004;350: 672–683.

    Article  CAS  PubMed  Google Scholar 

  45. Rius J, Guma M, Schachtrup C, et al. NF-kappaB links innate immunity to the hypoxic response through transcriptional egulation of HIF-1alpha. Nature. 2008;453:807–811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Schiessl B. Inflammatory response in preeclampsia. Mol Aspects Med. 2007;28:210–219.

    Article  CAS  PubMed  Google Scholar 

  47. Kanasaki K, Palmsten K, Sugimoto H, et al. Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia. Nature. 2008;453:1117–1121.

    Article  CAS  PubMed  Google Scholar 

  48. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet. 2008;371:75–84.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Challis JRG, Matthews SG, Gibb W, Lye SJ. Endocrine and paracrine regulation of birth at term and preterm. Endocr Rev. 2000;21:514–550.

    CAS  PubMed  Google Scholar 

  50. Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery. N Engl J Med. 2000;342: 1500–1507.

    Article  CAS  PubMed  Google Scholar 

  51. Osman I, Young A, Ledingham MA, et al. Leukocyte density and pro-inflammatory cytokine expression in human fetal membranes, decidua, cervix and myometrium before and during labour at term. Mol Hum Reprod. 2003;9:41–45.

    Article  CAS  PubMed  Google Scholar 

  52. Young A, Thomson AJ, Ledingham M, Jordan F, Greer IA, Norman JE. Immunolocalization of proinflammatory cytokines in myometrium, cervix, and fetal membranes during human parturition at term. Biol Reprod. 2002;66:445–449.

    Article  CAS  PubMed  Google Scholar 

  53. King AE, Kelly RW, Sallenave JM, Bocking AD, Challis JR. Innate immune defences in the human uterus during pregnancy. Placenta. 2007;28:1099–1106.

    Article  CAS  PubMed  Google Scholar 

  54. Thomson AJ, Telfer JF, Young A, et al. Leukocytes infiltrate the myometrium during human parturition: further evidence that labour is an inflammatory process. Hum Reprod. 1999;14: 229–236.

    Article  CAS  PubMed  Google Scholar 

  55. Osman I, Young A, Jordan F, Greer IA, Norman JE. Leukocyte density and proinflammatory mediator expression in regional human fetal membranes and decidua before and during labor at term. J Soc Gynecol Investig. 2006;13:97–103.

    Article  CAS  PubMed  Google Scholar 

  56. Haddad R, Tromp G, Kuivaniemi H, et al. Human spontaneous labor without histologic chorioamnionitis is characterized by an acute inflammation gene expression signature. Am J Obstet Gynecol. 2006;195:394.e1–24.

    Google Scholar 

  57. Hollier LM, Rivera MK, Henninger E, Gilstrap LC 3rd, Marshall GD Jr. T helper cell cytokine profiles in preterm labor. Am J Reprod Immunol. 2004;52:192–196.

    Article  PubMed  Google Scholar 

  58. Harger JH, Hsing AW, Tuomala RE, et al. Risk factors for preterm premature rupture of fetal membranes: a multicenter case-control study. Am J Obstet Gynecol. 1990;163(1 pt 1): 130–137.

    Article  CAS  PubMed  Google Scholar 

  59. Mackman N. Role of tissue factor in hemostasis, thrombosis, and vascular development. Arterioscler Thromb Vasc Biol. 2004;24:1015–1022.

    Article  CAS  PubMed  Google Scholar 

  60. Elovitz MA, Baron J, Phillippe M. The role of thrombin in pre-term parturition. Am J Obstet Gynecol. 2001;185:1059–1063.

    Article  CAS  PubMed  Google Scholar 

  61. Rosen T, Kuczynski E, O’Neill LM, Funai EF, Lockwood CJ. Plasma levels of thrombin-antithrombin complexes predict preterm premature rupture of the fetal membranes. J Matern Fetal Med. 2001;10:297–300.

    Article  CAS  PubMed  Google Scholar 

  62. Chaiworapongsa T, Espinoza J, Yoshimatsu J, et al. Activation of coagulation system in preterm labor and preterm premature rupture of membranes. J Matern Fetal Neonatal Med. 2002;11: 368–373.

    Article  CAS  PubMed  Google Scholar 

  63. Coughlin SR. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J Thromb Haemost. 2005;3: 1800–1814.

    Article  CAS  PubMed  Google Scholar 

  64. Moore RM, Mansour JM, Redline RW, Mercer BM, Moore JJ. The physiology of fetal membrane rupture: insight gained from the determination of physical properties. Placenta. 2006;27:1037–1051.

    Article  CAS  PubMed  Google Scholar 

  65. Rosen T, Schatz F, Kuczynski E, Lam H, Koo AB, Lockwood CJ. Thrombin-enhanced matrix metalloproteinase-1 expression: a mechanism linking placental abruption with premature rupture of the membranes. J Matern Fetal Neonatal Med. 2002;11:11–17.

    Article  CAS  PubMed  Google Scholar 

  66. Mackenzie AP, Schatz F, Krikun G, Funai EF, Kadner S, Lockwood CJ. Mechanisms of abruption-induced premature rupture of the fetal membranes: Thrombin enhanced decidual matrix metalloproteinase-3 (stromelysin-1) expression. Am J Obstet Gynecol. 2004;191:1996–2001.

    Article  CAS  PubMed  Google Scholar 

  67. Lockwood CJ, Toti P, Arcuri F, et al. Mechanisms of abruption-induced premature rupture of the fetal membranes: thrombin-enhanced interleukin-8 expression in term decidua. Am J Pathol. 2005;167:1443–1449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Baggiolini M, Dewald B, Moser B. Human chemokines: an update. Annu Rev Immunol. 1997;15:675–705.

    Article  CAS  PubMed  Google Scholar 

  69. Birkedal-Hansen H, Moore WG, Bodden MK, et al. Matrix metalloproteinases: a review. Crit Rev Oral Biol Med. 1993;4: 197–250.

    Article  CAS  PubMed  Google Scholar 

  70. Helmig BR, Romero R, Espinoza J, et al. Neutrophil elastase and secretory leukocyte protease inhibitor in prelabor rupture of membranes, parturition and intra-amniotic infection. J Matern Fetal Neonatal Med. 2002;12:237–246.

    Article  CAS  PubMed  Google Scholar 

  71. Matta P, Lockwood CJ, Schatz F, et al. Thrombin regulates monocyte chemoattractant protein-1 expression in human first trimester and term decidual cells. Am J Obstet Gynecol. 2007;196:268.e1–8.

    Article  CAS  Google Scholar 

  72. Jones SA. Directing transition from innate to acquired immunity: defining a role for IL-6. J Immunol. 2005;175:3463–3468.

    Article  CAS  PubMed  Google Scholar 

  73. Viganò P, Cintorino M, Schatz F, Lockwood CJ, Arcuri F. The role of macrophage migration inhibitory factor in maintaining the immune privilege at the fetal-maternal interface. Semin Immunopathol. 2007;29:135–150.

    Article  PubMed  CAS  Google Scholar 

  74. Shim SS, Romero R, Hong JS, et al. Clinical significance of intra-amniotic inflammation in patients with preterm premature rupture of membranes. Am J Obstet Gynecol. 2004;191: 1339–1345.

    Article  PubMed  Google Scholar 

  75. Bryant-Greenwood GD, Kern A, Yamamoto SY, Sadowsky DW, Novy MJ. Relaxin and the human fetal membranes. Reprod Sci. 2007;14(suppl 8):42–45.

    Article  CAS  PubMed  Google Scholar 

  76. Krikun G, Lockwood CJ, Abrahams VM, Mor G, Paidas M, Guller S. Expression of Toll-like receptors in the human decidua. Histol Histopathol. 2007;22:847–854.

    CAS  PubMed  Google Scholar 

  77. Beutler B. Inferences, questions and possibilities in Toll-like receptor signalling. Nature. 2004;430:257–263.

    Article  CAS  PubMed  Google Scholar 

  78. Myatt L, Lye SJ. Expression, localization and function of prostaglandin receptors in myometrium. Prostaglandins Leukot Essent Fatty Acids. 2004;70:137–148.

    Article  CAS  PubMed  Google Scholar 

  79. Sun K, Qu X, Gao L, Myatt L. Dexamethasone fails to inhibit the induction of cytosolic phospholipase A(2) expression by interleukin-1beta in cultured primary human amnion fibroblasts. Placenta. 2006;27:164–170.

    Article  CAS  PubMed  Google Scholar 

  80. Sun K, Ma R, Cui X, et al. Glucocorticoids induce cytosolic phospholipase A2 and prostaglandin H synthase type 2 but not microsomal prostaglandin E synthase (PGES) and cytosolic PGES expression in cultured primary human amnion cells. J Clin Endocrinol Metab. 2003;88:5564–5571.

    Article  CAS  PubMed  Google Scholar 

  81. Sennström MB, Ekman G, Westergren-Thorsson G, et al. Human cervical ripening, an inflammatory process mediated by cytokines. Mol Hum Reprod. 2000;6:375–381.

    Article  CAS  PubMed  Google Scholar 

  82. Xu P, Alfaidy N, Challis JR. Expression of matrix metalloproteinase (MMP)-2 and MMP-9 in human placenta and fetal membranes in relation to preterm and term labor. J Clin Endocrinol Metab. 2002;87:1353–1361.

    Article  CAS  PubMed  Google Scholar 

  83. Riley SC, Leask R, Denison FC, Wisely K, Calder AA, Howe DC. Secretion of tissue inhibitors of matrix metalloproteinases by human fetal membranes, decidua and placenta at parturition. J Endocrinol. 1999;162:351–359.

    Article  CAS  PubMed  Google Scholar 

  84. Pollard JK, Mitchell MD. Intrauterine infection and the effects of inflammatory mediators on prostaglandin production by myometrial cells from pregnant women. Am J Obstet Gynecol. 1996;174:682–686.

    Article  CAS  PubMed  Google Scholar 

  85. Slater DM, Dennes WJ, Campa JS, Poston L, Bennett PR. Expressionofcyclo-oxygenasetypes-1 and-2inhumanmyometrium throughout pregnancy. Mol Hum Reprod. 1999;5: 880–884.

    Article  CAS  PubMed  Google Scholar 

  86. Zuo J, Lei ZM, Rao CV, Pietrantoni M, Cook VD. Differential cyclooxygenase-1 and -2 gene expression in human myometria from preterm and term deliveries. J Clin Endocrinol Metab. 1994;79:894–899.

    CAS  PubMed  Google Scholar 

  87. Rauk PN, Friebe-Hoffmann U, Winebrenner LD, Chiao JP. Interleukin-6 up-regulates the oxytocin receptor in cultured uterine smooth muscle cells. Am J Reprod Immunol. 2001;45: 148–153.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Felice Petraglia MD.

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Challis, J.R., Lockwood, C.J., Myatt, L. et al. Inflammation and Pregnancy. Reprod. Sci. 16, 206–215 (2009). https://doi.org/10.1177/1933719108329095

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