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Baseline TNFα Operational Capacity in Fetal and Maternal Circulation Prior to the Onset of Labor: “Tuned for Different Purposes”

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Abstract

Objective

In this study, we sought to characterize the tumor necrosis factor α (TNFα) baseline operational capacity in mature fetuses and their mothers prior to the onset of labor.

Materials and Methods

We used an experimental pregnant nonhuman primate model to measure the plasma concentration of TNFα, TNF transmembrane receptor I (TNFRI), and TNFRII with validated enzyme-linked immunosorbent assays. Coefficients of correlations between the maternal and the fetal values and the soluble TNFα, TNFRI, or TNFRII concentrations and ratios were calculated.

Results

The TNFα/TNFRI ratio was 3 times lower in fetal circulation than in maternal circulation. No correlations were noted between the maternal and the fetal TNFα, TNFRI, or TNFRII plasma concentrations.

Conclusions

These findings suggest that the fetal and maternal baseline circulatory operational capacities of TNFα are independent of each other and tuned differently. This differential regulation of TNFα in fetal and maternal circulation at the end of pregnancy may be guided to protect the fetus from the systemic inflammatory response that is essential for the mechanisms of labor to proceed in the mother.

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References

  1. Bazzoni F, Beutler B. The tumor necrosis factor ligand and receptor families. N Engl J Med. 1996; 334(26):1717–1725.

    Article  CAS  PubMed  Google Scholar 

  2. Ruddle NH. Tumor necrosis factor (TNF-alpha) and lymphotoxin (TNF-beta). Curr Opin Immunol. 1992;4(3):327–332.

    Article  CAS  PubMed  Google Scholar 

  3. Vanden Berghe W, Vermeulen L, De Wilde G, De Bosscher K, Boone E, Haegeman G. Signal transduction by tumor necrosis factor and gene regulation of the inflammatory cytokine interleukin-6. Biochem Pharmacol. 2000;60(8):1185–1195.

    Article  Google Scholar 

  4. Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A. 1975;72(9):3666–3670.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Beutler B, Greenwald D, Hulmes JD, et al. Identity of tumour necrosis factor and the macrophage-secreted factor cachectin. Nature. 1985;316(6028):552–554.

    Article  CAS  PubMed  Google Scholar 

  6. Vilcek J, Lee TH. Tumor necrosis factor. New insights into the molecular mechanism of its multiple actions. J Biol Chem. 1991;266(12):7313.

  7. Davis JM, Narachi MA, Alton NK, Arakawa T. Structure of human tumor necrosis factor alpha derived from recombinant DNA. Biochemistry. 1987;26(5):1322–1326.

    Article  CAS  PubMed  Google Scholar 

  8. Jones E, Stuart D, Walker N. Structure of tumour necrosis factor. Nature. 1989;338(6212):225–228.

    Article  CAS  PubMed  Google Scholar 

  9. Calleja-Agius J, Muttukrishna S, Jauniaux E. The role of tumor necrosis factor-receptors in pregnancy with normal and adverse outcome. Int J Interferon Cytokine Mediator Res. 2012;4:1–15.

    Article  CAS  Google Scholar 

  10. Dembic Z, Loetscher H, Gubler U, et al. Two human TNF receptors have similar extracellular, but distinct intracellular, domain sequences. Cytokine. 1990;2(4):231–237.

    Article  CAS  PubMed  Google Scholar 

  11. Aderka D, Engelmann H, Shemer-Avni Y, et al Variation in serum levels of the soluble TNF receptors among healthy individuals. Lymphokine Cytokine Res. 1992;11(3):157–159.

    CAS  PubMed  Google Scholar 

  12. Porteu F, Nathan C. Shedding of tumor necrosis factor receptors by activated human neutrophils. J Exp Med. 1990;172(2): 599–607.

    Article  CAS  PubMed  Google Scholar 

  13. Seckinger P, Isaaz S, Dayer JM. Purification and biologic characterization of a specific tumor necrosis factor alpha inhibitor. J Biol Chem. 1989;264(20):11966–11973.

    CAS  PubMed  Google Scholar 

  14. Engelmann H, Novick D, Wallach D. Two tumor necrosis factor-binding proteins purified from human urine. Evidence for immunological cross-reactivity with cell surface tumor necrosis factor receptors. J Biol Chem. 1990;265(3):1531–1536.

    CAS  PubMed  Google Scholar 

  15. Olsson I, Lantz M, Nilsson E, et al Isolation and characterization of a tumor necrosis factor binding protein from urine. Eur J Haematol. 1989;42(3):270–275.

    Article  CAS  PubMed  Google Scholar 

  16. Haider S, Knöfler M. Human tumour necrosis factor: physiological and pathological roles in placenta and endometrium. Placenta. 2009;30(2):111–123.

    Article  CAS  PubMed  Google Scholar 

  17. Chen HL, Yang YP, Hu XL, Yelavarthi KK, Fishback JL, Hunt JS. Tumor necrosis factor alpha mRNA and protein are present in human placental and uterine cells at early and late stages of gestation. Am J Pathol. 1991;139(2):327–335.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Harris LK, Keogh RJ, Wareing M, et al Invasive trophoblasts stimulate vascular smooth muscle cell apoptosis by a fas ligand-dependent mechanism. Am J Pathol. 2006;169(5):1863–1874.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Keogh RJ, Harris LK, Freeman A, et al Fetal-derived trophoblast use the apoptotic cytokine tumor necrosis factor-alpha-related apoptosis-inducing ligand to induce smooth muscle cell death. Circ Res. 2007;100(6):834–841.

    Article  CAS  PubMed  Google Scholar 

  20. Witkin SS, Liu HC, Davis OK, Rosenwaks Z. Tumor necrosis factor is present in maternal sera and embryo culture fluids during in vitro fertilization. J Reprod Immunol. 1991;19(1):85–93.

    Article  CAS  PubMed  Google Scholar 

  21. Yang Y, Yelavarthi KK, Chen HL, Pace JL, Terranova PF, Hunt JS. Molecular, biochemical, and functional characteristics of tumor necrosis factor-alpha produced by human placental cytotrophoblastic cells. J Immunol. 1993;150(12): 5614–5624.

    CAS  PubMed  Google Scholar 

  22. King A, Jokhi PP, Smith SK, Sharkey AM, Loke YW. Screening for cytokine mRNA in human villous and extravillous trophoblasts using the reverse-transcriptase polymerase chain reaction (RT-PCR). Cytokine. 1995;7(4):364–371.

    Article  CAS  PubMed  Google Scholar 

  23. Yelavarthi KK, Hunt JS. Analysis of p60 and p80 tumor necrosis factor-alpha receptor messenger RNA and protein in human placentas. Am J Pathol. 1993;143(4):1131–1141.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Knofler M, Mosl B, Bauer S, Griesinger G, Husslein P. TNF-alpha/TNFRI in primary and immortalized first trimester cytotrophoblasts. Placenta. 2000;21(5–6):525–535.

    Article  CAS  PubMed  Google Scholar 

  25. Boyle JJ, Weissberg PL, Bennett MR. Tumor necrosis factor-alpha promotes macrophage-induced vascular smooth muscle cell apoptosis by direct and autocrine mechanisms. Arterioscler Thromb Vasc Biol. 2003;23(9):1553–1558.

    Article  CAS  PubMed  Google Scholar 

  26. Santolaya-Forgas J, Van Hook J, Edwin S, et al. Maternal plasma and celomic fluid concentration of TNFα, sTNFR-1, sTNFR-2 and RANTES in extraembryonic celomic fluid in pregnant baboons. Reprod Sci. 2006;13 suppl:(SGI Filename: 950579).

  27. Austgulen R, Liabakk NB, Brockhaus M, Espevik T. Soluble TNF receptors in amniotic fluid and in urine from pregnant women. J Reprod Immunol. 1992;22(2):105–16.

    Article  CAS  PubMed  Google Scholar 

  28. Brown MD, Feairheller DL, Thakkar S, Veerabhadrappa P, Park J-Y. Racial differences in tumor necrosis factor-α-induced endothelial microparticles and interleukin-6 production. Vasc Health Risk Manag. 2011:7 541–550.

  29. Stonek F, Bentz EK, Hafner E, et al. A tumor necrosis factor-α promoter polymorphism and pregnancy complications: results of a prospective cohort study in 1652 pregnant women. Reprod Sci. 2007;14(5):425–429.

    Article  CAS  PubMed  Google Scholar 

  30. Lambin S, van Bree R, Vergote I, Verhaeghe J. Chronic tumor necrosis factor-α infusion in gravid C57Bl6/J mice accelerates adipose tissue development in female offspring. J Soc Gynecol Investig. 2006;13(8):558–565.

    Article  CAS  PubMed  Google Scholar 

  31. Gropper MA. Evidence-based management of critically ill patients: analysis and implementation. Anesth Analg. 2004; 99(2):566–572.

    Article  PubMed  Google Scholar 

  32. Tartaglia LA, Goeddel DV. Two TNF receptors. Immunol Today. 1992;13(5):151–153.

    Article  CAS  PubMed  Google Scholar 

  33. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest. 2009;136(5 Suppl):e28.

  34. Naworth PP, Stern DM. Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med. 1986;163(3): 740–745.

    Article  Google Scholar 

  35. Russell JA. Management of sepsis. N Engl J Med. 2006;355(16): 1699–1713.

    Article  CAS  PubMed  Google Scholar 

  36. Kerschensteiner M, Meinl E, Hohlfeld R. Neuro-immune crosstalk in CNS diseases. Neuroscience. 2009;158(3): 1122–1132.

    Article  CAS  PubMed  Google Scholar 

  37. Van Zee KJ, Kohno T, Fischer E, Rock CS, Moldawer LL, Lowry SF. Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor alpha in vitro and in vivo. Proc Natl Acad Sci U S A. 1992;89(11):4845–4849.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Girardin E, Roux-Lombard P, Grau GE, Suter P, Gallati H, Dayer JM. Imbalance between tumour necrosis factor-alpha and soluble TNF receptor concentrations in severe meningococcaemia. The J5 Study Group. Immunology. 1992;76(1):20–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Spinas GA, Keller U, Brockhaus M. Release of soluble receptors for tumor necrosis factor (TNF) in relation to circulating TNF during experimental endotoxinemia. J Clin Invest. 1992;90(2):533–536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Elliott MJ, Maini RN, Feldmann M, et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet. 1994;344(8930):1105–1110.

    Article  CAS  PubMed  Google Scholar 

  41. Matsuda T, Nakajima T, Hattori S, et al. Necrotizing funisitis: clinical significance and association with chronic lung disease in premature infants. Am J Obstet Gynecol. 1997;177(6): 1402–1407.

    Article  CAS  PubMed  Google Scholar 

  42. Redline RW, Wilson-Costello D, Hack M. Placental and other perinatal risk factors for chronic lung disease in very low birth weight infants. Pediatr Res. 2002;52(5):713–719.

    Article  PubMed  Google Scholar 

  43. Santolaya-Forgas J, Mehta SH, Castracane VD. A study to determine if acute maternal fetal hyperglycemia/insulinemia induces leptin production during pregnancy. Horm Metab Res. 2006;38(9):598–602.

    Article  CAS  PubMed  Google Scholar 

  44. Santolaya-Forgas J, Romero R, Mehendale R. The effect of continuous morphine administration on maternal plasma oxytocin concentration and uterine contractions after open fetal surgery. J Matern Fetal Neonatal Med. 2006;19(4):231–232.

    Article  CAS  PubMed  Google Scholar 

  45. Oberyszyn TM. Inflammation and wound healing. Front Biosci. 2007;12:2993–2999.

    Article  CAS  PubMed  Google Scholar 

  46. Kniss DA, Zimmerman PD, Garver CL, Fertel RH. Interleukin-1 receptor antagonist blocks interleukin-1-induced expression of cyclooxygenase-2 in endometrium. Am J Obstet Gynecol. 1997; 177(3):559–567.

    Article  CAS  PubMed  Google Scholar 

  47. Imseis HM, Zimmerman PD, Samuels P, Kniss DA. Tumour necrosis factor-alpha induces cyclo-oxygenase-2 gene expression in first trimester trophoblasts: suppression by glucocorticoids and NSAIDs. Placenta. 1997;18(7):521–526.

    Article  CAS  PubMed  Google Scholar 

  48. Pomini F, Caruso A, Challis JR. Interleukin-10 modifies the effects of interleukin-1beta and tumor necrosis factor-alpha on the activity and expression of prostaglandin H synthase-2 and the NAD+-dependent 15-hydroxyprostaglandin dehydrogenase in cultured term human villous trophoblast and chorion trophoblast cells. J Clin Endocrinol Metab. 1999;84:4645–4651.

    CAS  PubMed  Google Scholar 

  49. Christiaens I, Zaragoza DB, Guilbert L, Robertson SA, Mitchell BF, Olson DM. Inflammatory processes in preterm and term parturition. J Reprod Immunol. 2008;79(1):50–57.

    Article  CAS  PubMed  Google Scholar 

  50. Ulug U, Goldman S, Ben-Shlomo I, Shalev E. Matrix metalloproteinase (MMP)-2 and MMP-9 and their inhibitor, TIMP-1, in human term decidua and fetal membranes: the effect of prostaglandin F(2alpha) and indomethacin. Mol Hum Reprod. 2001;7(12):1187–1193.

    Article  CAS  PubMed  Google Scholar 

  51. Dudley DJ. Immunoendocrinology of preterm labor: the link between corticotropin-releasing hormone and inflammation. Am J Obstet Gynecol. 1999;180(1 Pt 3):S251–S256.

    Article  CAS  PubMed  Google Scholar 

  52. Kossintseva I, Wong S, Johnstone E, Guilbert L, Olson DM, Mitchell BF. Proinflammatory cytokines inhibit human placental 11beta-hydroxysteroid dehydrogenase type 2 activity through Ca2+ and cAMP pathways. Am J Physiol Endocrinol Metab. 2006;290(2):E282-E288.

    Article  CAS  PubMed  Google Scholar 

  53. Lahra MM, Beeby PJ, Jeffery HE. Intrauterine inflammation, neonatal sepsis, and chronic lung disease: a 13-year hospital cohort study. Pediatrics. 2009;123(5):1314–1319.

    Article  PubMed  Google Scholar 

  54. Redline RW. Inflammatory responses in the placenta and umbilical cord. Semin Fetal Neonatal Med. 2006;11(5):296–301.

    Article  PubMed  Google Scholar 

  55. Lappen JR, Keene M, Lore M, Grobman WA, Gossett DR. Existing models fail to predict sepsis in an obstetric population with intrauterine infection. Am J Obstet Gynecol. 2010;203(6): 573.e1–5.

    Article  Google Scholar 

  56. Mittendorf R, Roizen N, Moawad A, Khoshnood B, Lee KS. Association between cerebral palsy and coagulase-negative staphylococci. Lancet. 1999;354(9193):1875–1876.

    Article  CAS  PubMed  Google Scholar 

  57. Perry VH, Cunningham C, Holmes C. Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol. 2007;7(2):161–167.

    Article  CAS  PubMed  Google Scholar 

  58. Kane SV, Acquah LA. Placental transport of immunoglobulins: a clinical review for gastroenterologists who prescribe therapeutic monoclonal antibodies to women during conception and pregnancy. Am J Gastroenterol. 2009;104(1):228–233.

    Article  CAS  PubMed  Google Scholar 

  59. Clowse ME. The use of anti-TNFα medications for rheumatologic disease in pregnancy. Int J Women’s Health. 2010;2:199–209.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology and Reproductive Sciences, University of Medicine and Dentistry New Jersey-Robert Wood Johnson Medical School, 125 Paterson Street, New Brunswick, NJ, 08901, USA

    Jacobo L. Santolaya MS-I, Lindsay Kugler MS-IV, Lissa Francois MD, Valeria Di Stefano MD, Gary A. Ebert MD, Bingbing Wang PhD & Joaquín Santolaya-Forgas MD, PhD

  2. Biological Research Laboratories, University of Oklahoma Health Science Center, Oklahoma City, OK, USA

    Roman Wolf DVM

Authors
  1. Jacobo L. Santolaya MS-I
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  2. Lindsay Kugler MS-IV
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  3. Lissa Francois MD
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  4. Valeria Di Stefano MD
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  5. Gary A. Ebert MD
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  6. Roman Wolf DVM
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  7. Bingbing Wang PhD
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  8. Joaquín Santolaya-Forgas MD, PhD
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Correspondence to Joaquín Santolaya-Forgas MD, PhD.

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Santolaya, J.L., Kugler, L., Francois, L. et al. Baseline TNFα Operational Capacity in Fetal and Maternal Circulation Prior to the Onset of Labor: “Tuned for Different Purposes”. Reprod. Sci. 20, 838–844 (2013). https://doi.org/10.1177/1933719112468953

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  • DOI: https://doi.org/10.1177/1933719112468953

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