Advertisement

Reproductive Sciences

, Volume 19, Issue 1, pp 43–54 | Cite as

Myometrial Tumor Necrosis Factor-α Receptors Increase With Gestation and Labor and Modulate Gene Expression Through Mitogen-Activated Kinase and Nuclear Factor-κB

  • Helen A. Alexander
  • Suren R. Sooranna
  • Leslie Myatt
  • Mark R. JohnsonEmail author
Article

Abstract

Previously, we found that myometrial tumor necrosis factor-α (TNF-α) messenger RNA (mRNA) expression did not increase with preterm or term labor. To further investigate the role of TNF-α in human labor, we studied TNF-α receptor (TNFR1A and B) expression, regulation, and associated intracellular signaling pathways in human myometrial samples obtained both before and after the onset of labor and in primary cultures of uterine smooth muscle cells (USMCs). We found that the mRNA expression of both receptors increased with advancing gestation and labor and protein levels of TNFR1B were significantly higher in term laboring myometrial samples than in nonlabor controls. Tumor necrosis factor-ᾳ treatment of USMCs activated all mitogen-activated protein kinase (MAPK) subtypes and nuclear factor κ-B (NF-κB). The TNF-α induced increases in the expression of TNFR1B and prostaglandin H synthase type 2 were reduced by inhibitors of NF-κB and MAPKs, respectively. The TNF-α induced increase in interleukin 8 (IL-8) appeared to be independent of MAPK and NF-κB pathway. These data suggest that the uterus may become more sensitive to the action of TNF-α with advancing gestation and labor and that TNF-α acts via MAPK and NF-κB to promote labor-associated gene expression.

Keywords

labor myometrium tumor necrosis factor-α inflammation pro-labor genes 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Lumley J. Defining the problem: the epidemiology of preterm birth. BJOG. 2003;110(suppl 20):3–7.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Wenstrom KD, Andrews WW, Hauth JC, Goldenberg RL, DuBard MB, Cliver SP. Elevated second-trimester amniotic fluid interleukin-6 levels predict delivery. Am J Obstet Gynecol. 1998; 178(3):546–550.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    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(1): 229–236.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Romero R, Brody DT, Oyarzun E, et al. Infection and labour. III. Interleukin-1: a signal for the onset of parturition. Am J Obstet Gynecol. 1989;160(5 pt 1):1117–1123.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Osmers RG, Bläser J, Kuhn W, Tschesche H. Interleukin-8 synthesis and the onset of labour. Obstet Gynecol. 1995;86(2):223–229.PubMedCrossRefGoogle Scholar
  6. 6.
    Keelan JA, Blumenstein M, Helliwell RJ, Sato TA, Marvin KW, Mitchell MD. Cytokines, prostaglandins and parturition—a review. Placenta. 2003;24(suppl A):S33–S46.PubMedCrossRefGoogle Scholar
  7. 7.
    Lundin-Schiller S, Mitchell MD. Prostaglandin production by human chorion leave cells in response to inflammatory mediators. Placenta. 1991;12(4):353–363.PubMedCrossRefGoogle Scholar
  8. 8.
    Khatun S, Kanayama N, Belavet H, Yonezawa M, Kobayashi T, Terao T. Interleukin-8 potentiates the effects of interleukin-1-induced uterine contractions. Hum Reprod. 1999;14(2): 560–565.PubMedCrossRefGoogle Scholar
  9. 9.
    Casey ML, Cox SM, Beutler B, Milewich L, MacDonald PC. Cachectin/tumour necrosis factor-alpha formation in human deciduas. Potential role for cytokines in infection-induced preterm labour. J Clin Invest. 1989;83(2):430–436.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Chwalisz K, Benson M, Scholz P, Daum J, Beier HM, Hegele-Hartung C. Cervical ripening with the cytokines interleukin 8, interleukin 1 beta and tumour necrosis factor alpha in guinea-pigs. Hum Reprod. 1994;9(11):2173–2181.PubMedCrossRefGoogle Scholar
  11. 11.
    Sadowsky DW, Adams KM, Gravett MG, Witkin SS, Novy MJ. Preterm labour is induced by intraamniotic infusions of interleukin-1beta and tumour necrosis factor- alpha but not by interleukin-6 or interleukin-8 in a nonhuman primate model. Am J Obstet Gynecol. 2006;195(6):1578–1589.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Romero R, Mazor M, Wu YK, et al. Infection in the pathogenesis of preterm labor. Seminars Perinatol. 1988;12(4):262–279.Google Scholar
  13. 13.
    Hertelendy F, Romero R, Molnár M, Todd H, Baldassare JJ. Cytokine-initiated transduction in human myometrial cells. Am J Reprod Immunol. 1993;30(2–3):49–57.PubMedCrossRefGoogle Scholar
  14. 14.
    Fitzgibbon J, Morrison JJ, Smith TJ, O’brien M. Modulation of human uterine smooth muscle cell collagen contractility by thrombin, Y-27632, TNF alpha and indomethacin. Reprod Biol Endocrinol. 2009;7:2.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Tattersall M, Engineer N, Khanjani S, et al. Pro-labour myometrial gene expression: are preterm labour and term labour the same? Reproduction. 2008;135(4):569–579.PubMedCrossRefGoogle Scholar
  16. 16.
    Bowen JM, Chamley L, Mitchell MD, Keelan JA. Cytokines of the placenta and extra-placental membranes: biosynthesis secretion and roles in establishment of pregnancy in women. Placenta. 2002;23(4):239–256.PubMedCrossRefGoogle Scholar
  17. 17.
    Maymon E, Ghezzi F, Edwin SS, et al. The tumor necrosis factor alpha and its soluble receptor profile in term and preterm parturition. Am J Obstet Gynecol. 1999;181(5 pt 1):1142–1148.PubMedCrossRefGoogle Scholar
  18. 18.
    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(2):445–449.PubMedCrossRefGoogle Scholar
  19. 19.
    Sehringer B, Schäfer WR, Wetzka B, Deppert WR, Brunner-Spahr R, Benedek E. Formation of proinflammatory cytokines in human term myometrium is stimulated by lipopolysaccharide but not by corticotrophin-releasing hormone. J Clin Endocrinol Metab. 2000;85(12):4859–4866.PubMedGoogle Scholar
  20. 20.
    Winkler M, Kemp B, Fischer DC, Maul H, Hlubek M, Rath W. Tissue concentrations of cytokines in the lower uterine segment during preterm parturition. J Perinat Med. 2001; 29(6):519–527.PubMedCrossRefGoogle Scholar
  21. 21.
    Bazzoni F, Beutler B. The Tumour necrosis factor ligand and receptor families. N Engl J Med. 1996;334(26):1717–1725.PubMedCrossRefGoogle Scholar
  22. 22.
    Legler DF, Micheau O, Doucey MA, Tschopp J, Bron C. Recruitment of TNF receptor 1 to lipid rafts is essential for TNFalpha-mediated NF-kappaB activation. Immunity. 2003;18(5):655–664.PubMedCrossRefGoogle Scholar
  23. 23.
    Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell. 2003; 114(2):181–190.PubMedCrossRefGoogle Scholar
  24. 24.
    Dempsey PW, Doyle SE, He JQ, Cheng G. The signaling adaptors and pathways activated by TNF superfamily. Cytokine Growth Factor Rev 2003;14(3–4):193–209.PubMedCrossRefGoogle Scholar
  25. 25.
    Steinborn A, Geisse M, Kaufmann M. Expression of cytokine receptors in the placenta in term and preterm labour. Placenta. 1998;19(2–3):165–170.PubMedCrossRefGoogle Scholar
  26. 26.
    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):105–116.PubMedCrossRefGoogle Scholar
  27. 27.
    Rose-John S, Heinrich PC. Soluble receptors for cytokines and growth factors: generation and biological function. Biochem J. 1994;300(pt 2):281–290.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Leroy M-J, Dallot E, Czerkiewicz I, Schmitz T, Breuiller-Fouche M. Inflammation of choriodecidua induces tumour necrosis factor alpha-mediated apoptosis of human myometrial cells. Biol Reprod. 2007;76(5):769–776.PubMedCrossRefGoogle Scholar
  29. 29.
    Tabibzadeh S, Zupi E, Babaknia A, Liu R, Marconi D, Romanini C. Site and menstrual cycle-dependent expression of proteins of the tumour necrosis factor (TNF) receptor family, and BCL-2 oncoprotein and phase-specific production of TNF alpha in human endometrium. Hum Reprod. 1995;10(2):277–286.CrossRefGoogle Scholar
  30. 30.
    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.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Pieber D, Allport VC, Hills F, Johnson M, Bennett PR. Interactions between progesterone receptor isoforms in myometrial cells in human labour. Mol Hum Reprod. 2001;7(9):875–879.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Reddy J, Chastagner P, Fiette L, Liu X, Thèze J. IL-2 induced tumour necrosis factor (TNF)-beta expression: further analysis in the IL-2 knockout model, and comparison with TNF-alpha, lymphotoxin-beta, TNFR1 and TNFR2 modulation. Int Immunol. 2001;13(2):135–147.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Dopp JM, Mackenzie-Graham A, Otero GC, Merrill JE. Differential expression, cytokine modulation, and specific functions of type-1 and type-2 tumour necrosis factor receptors in rat glia. J Neuroimmunol. 1997;75(1–2):104–112.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Choi SJ, Lee KH, Park HS, Kim SK, Koh CM, Park JY. Differential expression, shedding, cytokine regulation and function of TNFR1 and TNFR2 in human fetal astrocytes. Yonsei Med J. 2005;46(6):818–826.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Roberts M, Luo X, Chegini N. Differential regulation of interleukins IL-13 and IL-15 by ovarian steroids, TNF-alpha and TGF-beta in human endometrial epithelial and stromal cells. Mol Hum Reprod. 2005;11(10):751–760.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Trefzer U, Brockhaus M, Lötscher H, et al. The 55-kD tumour necrosis factor receptor on human keratinocytes is regulated by tumour necrosis factor-alpha and by ultraviolet B radiation. J Clin Invest. 1993;92(1):462–470.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Ohe H, Takashiba S, Naruishi K, et al. Tumour necrosis factor-α (TNF-α)-induced and interleukin-1β (IL-1β)-induced shedding of TNF Receptors from gingival fibroblasts. J Interferon Cytokine Res. 2000;20(12):1077–1082.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Yang CM, Luo SF, Wang CC, et al. Tumour necrosis factor-α-and interleukin-1β-stimulated cell proliferation through activation of mitogen-activated protein kinase in canine tracheal smooth muscle cells. B J Pharmacol. 2000;130(4):891–899.CrossRefGoogle Scholar
  39. 39.
    Lin CC, Hsiao LD, Chien CS, Lee CW, Hsieh JT, Yang CM. Tumour necrosis factor-α-induced cyclooxygenase-2 expression in human tracheal smooth muscle cells: involvement of p42/44 and p38 mitogen-activated protein kinases and nuclear factor-KB. Cell Signal. 2004;16(5):597–607.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Lee CW, Lin WN, Lin CC, et al. Transcriptional regulation of VCAM-1 expression by tumour necrosis factor-alpha in human tracheal smooth muscle cells: involvement of MAPKs, NF-kappaB, p300, and histone acetylation. J Cell Physiol. 2006;207(1):174–186.PubMedCrossRefGoogle Scholar
  41. 41.
    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(6):2317–2326.PubMedCrossRefGoogle Scholar
  42. 42.
    Zaragoza DB, Wilson RR, Mitchell BF, Olson DM. The interleu-kin 1beta-induced expression of human prostaglandin F2alpha receptor messenger RNA in human myometrial-derived ULTR cells requires the transcription factor, NFkappaB. Biol Reprod. 2006;75(5):697–704.PubMedCrossRefGoogle Scholar
  43. 43.
    von Brandenstein MG, Ngum Abety A, Depping R, et al. A p38–p65 transcription complex induced by endothelin-1 mediates signal transduction in cancer cells. Biochim Biophys Acta. 2008;1783(9):1613–1622.CrossRefGoogle Scholar
  44. 44.
    Hu J, Haseebuddin M, Young M, Colburn NH. Suppression of p65 phosphorylation coincides with inhibition of IkappaBalpha polyubiquitination and degradation. Mol Carcinog. 2005;44(4): 274–284.PubMedCrossRefGoogle Scholar
  45. 45.
    Vermeulen L, De Wilde G, Van Damme P, Vanden Berghe W, Haegeman G. Transcriptional activation of the NF-kappaB p65 subunit by mitogen- and stress-activated protein kinase-1 (MSK1). EMBO J. 2003;22(6):1313–1324.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Osorio-Fuentealba C, Valdés JA, Riquelme D, Hidalgo J, Hidalgo C, Carrasco MA. Hypoxia stimulates via separate pathways ERK phosphorylation and NF-kappaB activation in skeletal muscle cells in primary culture. J Appl Physiol. 2009;106(4): 1301–1310.PubMedCrossRefGoogle Scholar
  47. 47.
    Chen YM, Chiang WC, Lin SL, Wu KD, Tsai TJ, Hsieh BS. Dual regulation of tumor necrosis factor-alpha-induced CCL2/monocyte chemoattractant protein-1 expression in vascular smooth muscle cells by nuclear factor-kappaB and activator protein-1: modulation by type III phosphodiesterase inhibition. J Pharmacol Exp Ther. 2004;309(3):978–986.PubMedCrossRefGoogle Scholar
  48. 48.
    Jang BC, Lim KJ, Paik JH, et al. Up-regulation of human beta-defensin 2 by interleukin-1beta in A549 cells: involvement of PI3K, PKC, p38 MAPK, JNK, and NF-kappaB. Biochem Biophys Res Commun. 2004;320(2):1026–1033.PubMedCrossRefGoogle Scholar
  49. 49.
    Wang HQ, Liu BQ, Gao Y, et al. Inhibition of the JNK signalling pathway enhances proteasome inhibitor-induced apoptosis of kidney cancer cells by suppression of BAG3 expression. B J Pharmacol. 2009;158(5):1405–1412.CrossRefGoogle Scholar
  50. 50.
    Zhang L, Ebenezer PJ, Dasuri K, Bruce-Keller AJ, Liu Y, Keller JN. Proteasome inhibition modulates kinase activation in neural cells: relevance to ubiquitination, ribosomes, and survival. J Neurosci Res. 2009;87(14):3231–3238.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Wu WT, Chi KH, Ho FM, Tsao WC, Lin WW. Proteasome inhibitors up-regulate haem oxygenase-1 gene expression: requirement of p38 MAPK (mitogen-activated protein kinase) activation but not of NF-kappaB (nuclear factor kappaB) inhibition. Biochem J. 2004; 379(Pt 3):587–593.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Hirsch E, Muhle RA, Mussalli GM, Blanchard R. Bacterially induced preterm labour in the mouse does not require maternal interleukin-1 signalling. Am J Obstet Gynecol. 2002;186(3):523–530.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Hirsch E, Filipovich Y, Mahendroo M. Signalling via the type I IL-1 and TNF receptors is necessary for bacterially induced preterm labor in a murine model. Am J Obstet Gynecol. 2006;194(5):1334–1340.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Society for Reproductive Investigation 2012

Authors and Affiliations

  • Helen A. Alexander
    • 1
  • Suren R. Sooranna
    • 1
  • Leslie Myatt
    • 2
  • Mark R. Johnson
    • 1
    • 3
    Email author
  1. 1.Imperial College Parturition Research Group, Academic Department of Obstetrics & GynaecologyImperial College School of Medicine, Chelsea and Westminster HospitalLondonUK
  2. 2.Center for Pregnancy and Newborn Research, Department of Obstetrics and GynecologyUniversity of Texas Health Science Center San AntonioSan AntonioUSA
  3. 3.Academic Department of Obstetrics & Gynaecology, Imperial College School of MedicineChelsea and Westminster HospitalLondonUK

Personalised recommendations