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Progestins Inhibit Tumor Necrosis Factor α—Induced Matrix Metalloproteinase 9 Activity via the Glucocorticoid Receptor in Primary Amnion Epithelial Cells

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Abstract

Progestins have been recommended for preterm birth prevention in high-risk women; however, their mechanism of action still remains an area of debate. Medroxyprogesterone acetate (MPA) has previously been shown to significantly inhibit tumor necrosis factor α (TNFα)-induced matrix metalloproteinase 9 (MMP9) messenger RNA (mRNA) expression and activity in primary amnion epithelial cells, a process that may lead to preterm premature rupture of membranes. A mechanism that explains MPA’s inhibition of TNFα-induced MMP9 mRNA expression and activity in primary amnion epithelial cells is unclear since these cells lack the classic nuclear progesterone receptor but express a membrane-associated progesterone receptor—progesterone receptor membrane component 1 (PGRMC1) along with the glucocorticoid receptor (GR). Primary amnion epithelial cells harvested from healthy term pregnant women at cesarean section were treated with PGRMC1 (to knockdown PGRMC1 expression), GR (to knockdown GR expression), or control small interfering RNA (siRNA; 10 nm) for 72 hours, pretreated with ethanol or MPA (10−6 M) for 6 hours, and then stimulated with or without TNFα 10 ng/mL for 24 hours. Real-time quantitative polymerase chain reaction and gelatin zymography were used to quantify MMP9 mRNA expression and activity, respectively. Experimental groups were compared using 1-way analysis of variance. Both TNFα-induced MMP9 mRNA expression and activity were significantly inhibited by pretreatment with MPA; however, only the inhibition of TNFα-induced MMP9 activity was partially reversed with PGRMC1 siRNA. However, GR siRNA reversed both the inhibition of TNFα-induced MMP9 mRNA expression and activity by MPA. This study demonstrates that MPA mediates its anti-inflammatory effects primarily through GR and partially through PGRMC1 in primary amnion epithelial cells.

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References

  1. Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. 2003;348(24):2379–2385.

    Article  CAS  PubMed  Google Scholar 

  2. Norman JE, Marlow N, Messow CM, et al. Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial. Lancet. 2016;387(10033):2106–2116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Nelson DB, McIntire DD, McDonald J, Gard J, Turrichi P, Leveno KJ. 17-alpha hydroxyprogesterone caproate did not reduce the rate of recurrent preterm birth in a prospective cohort study. Am J Obstet Gynecol. 2017;216(6):600.e601–600.e609.

    Article  CAS  Google Scholar 

  4. Crowther CA, Ashwood P, McPhee AJ, et al. Vaginal progesterone pessaries for pregnant women with a previous preterm birth to prevent neonatal respiratory distress syndrome (the PROGRESS Study): a multicentre, randomised, placebo-controlled trial. Plos Med. 2017;14(9):e1002390.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Hassan SS, Romero R, Vidyadhari D, et al. Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol. 2011;38(1):18–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Allen TK, Feng L, Nazzal M, Grotegut CA, Buhimschi IA, Murtha AP. The effect of progestins on tumor necrosis factor α-induced matrix metalloproteinase-9 activity and gene expression in human primary amnion and chorion cells in vitro. Anesth Analg. 2015;120(5):1085–1094.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Guoyang L, Abrahams VM, Tadesse S, et al. Progesterone inhibits basal and TNF-α-induced apoptosis in fetal membranes: a novel mechanism to explain progesterone-mediated prevention of preterm birth. Reprod Sci. 2010;17(6):532–539.

    Article  CAS  Google Scholar 

  8. Kumar D, Springel E, Moore RM, et al. Progesterone inhibits in vitro fetal membrane weakening. Am J Obstet Gynecol. 2015;213(4):520.e1–520.e9.

    Article  CAS  Google Scholar 

  9. Kumar D, Moore RM, Mercer BM, et al. In an in-vitro model using human fetal membranes, 17-α hydroxyprogesterone caproate is not an optimal progestogen for inhibition of fetal membrane weakening. Am J Obstet Gynecol. 2017;217(6):695.e1–695.e14.

    Article  CAS  Google Scholar 

  10. Athayde N, Edwin SS, Romero R, et al. A role for matrix metalloproteinase-9 in spontaneous rupture of the fetal membranes. Am J Obstet Gynecol. 1998;179(5):1248–1253.

    Article  CAS  PubMed  Google Scholar 

  11. Fortunato SJ, Menon R. Distinct molecular events suggest different pathways for preterm labor and premature rupture of membranes. Am J Obstet Gynecol. 2001;184(7):1399–1406.

    Article  CAS  PubMed  Google Scholar 

  12. Uchide K, Ueno H, Inoue M, Sakai A, Fujimoto N, Okada Y. Matrix metalloproteinase-9 and tensile strength of fetal membranes in uncomplicated labor. Obstet Gynecol. 2000;95(6, Part 1):851–855.

    CAS  PubMed  Google Scholar 

  13. Vadillo-Ortega F, González-Avila G, Furth EE, et al. 92-kd type IV collagenase (matrix metalloproteinase-9) activity in human amniochorion increases with labor. Am J Pathol. 1995;146(1):148–156.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Ferrand PE, Parry S, Sammel M, et al. A polymorphism in the matrix metalloproteinase-9 promoter is associated with increased risk of preterm premature rupture of membranes in African Americans. Mol Hum Rerood. 2002;8(5):494–501.

    Article  CAS  Google Scholar 

  15. Lei H, Kalluri R, Furth EE, Baker AH, Strauss JF III. Rat amnion type IV collagen composition and metabolism: implications for membrane breakdown. Biol Reprod. 1999;60(1):176–182.

    Article  CAS  PubMed  Google Scholar 

  16. Kumar D, Fung W, Moore RM, et al. Proinflammatory cytokines found in amniotic fluid induce collagen remodeling, apoptosis, and biophysical weakening of cultured human fetal membranes. Biol Reprod. 2006;74(1):29–34.

    Article  PubMed  CAS  Google Scholar 

  17. Allen TK, Feng L, Grotegut CA, Murtha AP. Progesterone receptor membrane component 1 as the mediator of the inhibitory effect of progestins on cytokine-induced matrix metalloproteinase 9 activity in vitro. Reprod Sci. 2014;21(2):260–268.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Merlino A, Welsh T, Erdonmez T, et al. Nuclear progesterone receptor expression in the human fetal membranes and decidua at term before and after labor. Reprod Sci. 2009;16(4):357–363.

    Article  CAS  PubMed  Google Scholar 

  19. Feng L, Ransom CE, Nazzal MK, et al. The role of progesterone and a novel progesterone receptor, progesterone receptor membrane component 1, in the inflammatory response of fetal membranes to ureaplasma parvum infection. Plos One. 2016;11(12):e0168102.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Feng L, Antczak B, Lan L, et al. Progesterone receptor membrane component 1 (PGRMC1) expression in fetal membranes among women with preterm premature rupture of the membranes (PPROM). Placenta. 2014;35(5):331–333.

    Article  CAS  PubMed  Google Scholar 

  21. Schindler AE, Campagnoli C, Druckmann R, et al. Classification and pharmacology of progestins. Maturitas. 2003;46(suppl 1):7–16.

    Article  CAS  Google Scholar 

  22. Lockwood CJ, Stocco C, Murk W, Kayisli UA, Funai EF, Schatz F. Human labor is associated with reduced decidual cell expression of progesterone, but not glucocorticoid, receptors. J Clin Endocrinol Metab. 2010;95(5):2271–2275.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sun M, Ramirez M, Challis JRG, Gibb W. Immunohistochemical localization of the glucocorticoid receptor in human fetal membranes and decidua at term and preterm delivery. J Endocrinol. 1996;149(2):243–248.

    Article  CAS  PubMed  Google Scholar 

  24. Capece A, Vasieva O, Meher S, Alfirevic Z, Alfirevic A. Pathway analysis of genetic factors associated with spontaneous preterm birth and pre-labor preterm rupture of membranes. PLoS One. 2014;9(9):e108578.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Liu C, Guo C, Wang W, et al. Inhibition of lysyl oxidase by cortisol regeneration in human amnion: implications for rupture of fetal membranes. Endocrinology. 2016;157(10):4055–4065.

    Article  CAS  PubMed  Google Scholar 

  26. Wang W, Liu C, Sun K. Induction of amnion epithelial apoptosis by cortisol via tPA/plasmin system. Endocrinology. 2016;157(11):4487–4498.

    Article  CAS  PubMed  Google Scholar 

  27. Lei K, Chen L, Georgiou EX, et al. Progesterone acts via the nuclear glucocorticoid receptor to suppress IL-1β-induced COX-2 expression in human term myometrial cells. Plos One. 2012;7(11):e50167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Casey ML, MacDonald PC. Interstitial collagen synthesis and processing in human amnion: a property of the mesenchymal cells. Biol Reprod. 1996;55(6):1253–1260.

    Article  CAS  PubMed  Google Scholar 

  29. Brink M, Humbel BM, De Kloet ER, Van Driel R. The unliganded glucocorticoid receptor is localized in the nucleus, not in the cytoplasm. Endocrinology. 1992;130(6):3575–3581.

    Article  CAS  PubMed  Google Scholar 

  30. Wikström AC, Bakke O, Okret S, Brönnegård M, Gustafsson JÅ. Intracellular localization of the glucocorticoid receptor: evidence for cytoplasmic and nuclear localization. Endocrinology. 1987;120(4):1232–1242.

    Article  PubMed  Google Scholar 

  31. Terzaghi L, Luciano AM, Dall’Acqua PC, Modina SC, Peluso JJ, Lodde V. PGRMC1 localization and putative function in the nucleolus of bovine granulosa cells and oocytes. Reproduction. 2018;155(3):273–282.

    Article  CAS  PubMed  Google Scholar 

  32. Thomas P, Pang Y, Dong J. Enhancement of cell surface expression and receptor functions of membrane progestin receptor α (mPRα) by progesterone receptor membrane component 1 (PGRMC1): evidence for a role of PGRMC1 as an adaptor protein for steroid receptors. Endocrinology. 2014;155(3):1107–1119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Xu J, Zeng C, Chu W, et al. Identification of the PGRMC1 protein complex as the putative sigma-2 receptor binding site. Nat Commun. 2011;2:380.

    Article  PubMed  CAS  Google Scholar 

  34. Peluso JJ, Pappalardo A, Losel R, Wehling M. Progesterone membrane receptor component 1 expression in the immature rat ovary and its role in mediating progesterone’s antiapoptotic action. Endocrinology. 2006;147(6):3133–3140.

    Article  CAS  PubMed  Google Scholar 

  35. Peluso JJ, Romak J, Liu X. Progesterone receptor membrane component-1 (PGRMC1) is the mediator of progesterone’s antiapoptotic action in spontaneously immortalized granulosa cells as revealed by PGRMC1 small interfering ribonucleic acid treatment and functional analysis of PGRMC1 mutations. Endocrinology. 2008;149(2):534–543.

    Article  CAS  PubMed  Google Scholar 

  36. Meng Y, Murtha AP, Feng L. Progesterone, inflammatory cytokine (TNF-α), and oxidative stress (H2O2) regulate progesterone receptor membrane component 1 expression in fetal membrane cells. Reprod Sci. 2016;23(9):1168–1178.

    Article  CAS  PubMed  Google Scholar 

  37. Dennis AP, O’Malley BW. Rush hour at the promoter: how the ubiquitin-proteasome pathway polices the traffic flow of nuclear receptor-dependent transcription. J Steroid Biochem Mol Biol. 2005;93(2):139–151.

    Article  CAS  PubMed  Google Scholar 

  38. Schulz M, Eggert M, Baniahmad A, Dostert A, Heinzel T, Renkawitz R. RU486-induced glucocorticoid receptor agonism is controlled by the receptor N terminus and by corepressor binding. J Biol Chem 2002. 2002;277(29):26238–26243.

    CAS  Google Scholar 

  39. Goldkrand JW, Schulte RL, Messer RH. Maternal and fetal plasma cortisol levels at parturition. Obstet Gynecol. 1976;47(1):41–45.

    CAS  PubMed  Google Scholar 

  40. Guo C, Wang W, Liu C, Myatt L, Sun K. Induction of PGF2α synthesis by cortisol through Gr dependent induction of CBR1 in human amnion fibroblasts. Endocrinology. 2014;155(8):3017–3024.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Smith R. Parturition. N Eng J Med. 2007;356(3):271–283.

    Article  CAS  Google Scholar 

  42. Copper RL, Goldenberg RL, Das A, et al. The preterm prediction study: maternal stress is associated with spontaneous preterm birth at less than thirty-five weeks’ gestation. Am J Obstet Gynecol. 1996;175(5):1286–1292.

    Article  CAS  PubMed  Google Scholar 

  43. Zhu P, Tao F, Hao J, Sun Y, Jiang X. Prenatal life events stress: implications for preterm birth and infant birthweight. Am J Obstet Gynecol. 2010;203(1):34.e31–34.e38.

    Article  Google Scholar 

  44. Christiaens I, Ang QW, Gordon LN, et al. Two novel genetic variants in the mineralocorticoid receptor gene associated with spontaneous preterm birth. BMC Med Genet. 2015;16:59.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Bream ENA, Leppellere CR, Cooper ME, et al. Candidate gene linkage approach to Identify DNA variants that predispose to preterm birth. Pediatr Res. 2013;73(2):135–141.

    Article  CAS  PubMed  Google Scholar 

  46. Peluso JJ, Liu X, Gawkowska A, Lodde V, Wu CA. Progesterone inhibits apoptosis in part by PGRMC1-regulated gene expression. Mol Cell Endocrinol. 2010;320(1–2):153–161.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Peluso JJ, Griffin D, Liu X, Horne M. Progesterone receptor membrane component-1 (PGRMC1) and PGRMC-2 interact to suppress entry into the cell cycle in spontaneously immortalized rat granulosa cells. Biol Reprod. 2014;91(5):104, 101–112.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Kabe Y, Nakane T, Koike I, et al. Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance. Nat Commun. 2016;7:11030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Sueldo C, Liu X, Peluso JJ. Progestin and AdipoQ Receptor 7, progesterone membrane receptor component 1 (PGRMC1), and PGRMC2 and their role in regulating progesterone’s ability to suppress human granulosa/luteal cells from entering into the cell cycle1. Biol Reprod. 2015;93(3):63, 1–11.

    Article  PubMed  CAS  Google Scholar 

  50. Mir SUR, Jin L, Craven RJ. Neutrophil gelatinase-associated lipocalin (NGAL) expression is dependent on the tumor-associated sigma-2 receptor S2RPgrmc1. J Biol Chem. 2012;287(18):14494–14501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 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, Part 1):130–137.

    Article  CAS  PubMed  Google Scholar 

  52. Holmgren PÅ, Olofsson JI. Preterm premature rupture of membranes and the associated risk for placental abruption. Inverse correlation to gestational length. Acta Obstet Gynecol Scand. 1997;76(8):743–747.

    Article  CAS  PubMed  Google Scholar 

  53. Kumar D, Schatz F, Moore RM, et al. The effects of thrombin and cytokines upon the biomechanics and remodeling of isolated amnion membrane, in vitro. Placenta. 2011;32(3):206–213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 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(6):1996–2001.

    Article  CAS  PubMed  Google Scholar 

  55. Mogami H, Keller PW, Shi H, Word RA. Effect of thrombin on human amnion mesenchymal cells, mouse fetal membranes, and preterm birth. J Biol Chem. 2014;289(19):13295–13307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Goldzieher JW. Double-blind trial of a progestin in habitual abortion. JAMA. 1964;188(7):651–654.

    Article  CAS  PubMed  Google Scholar 

  57. Brenner WE, Hendricks CH. Effect of medroxyprogesterone acetate upon the duration and characteristics of human gestation and labor. Am J Obstet Gynecol. 1962;83(8):1094–1098.

    Article  CAS  PubMed  Google Scholar 

  58. Goldstein P, Berrier J, Rosen S, Sacks HS, Chalmers TC. A meta-analysis of randomized control trials of progestational agents in pregnancy. Br J Obstet Gynaecol. 1989;96(3):265–274.

    Article  CAS  PubMed  Google Scholar 

  59. Oakley RH, Cidlowski JA. The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease. J Allergy Clinical Immunol. 2013;32(5):1033–1044.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Anesthesiology, Duke University Hospital, Durham, NC, 27710, USA

    Terrence K. Allen MBBS, MHS, FRCA

  2. Department of Obstetrics and Gynecology, Duke University Hospital, Durham, NC, USA

    Matthew N. Nazzal BS, Liping Feng MD & Amy P. Murtha MD

  3. Nationwide Children’s Hospital, Perinatal Research Institute, Columbus, OH, USA

    Irina A. Buhimschi MD

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  1. Terrence K. Allen MBBS, MHS, FRCA
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  2. Matthew N. Nazzal BS
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  3. Liping Feng MD
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  4. Irina A. Buhimschi MD
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  5. Amy P. Murtha MD
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Correspondence to Terrence K. Allen MBBS, MHS, FRCA.

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Authors’ Note

Terrence K. Allen studied the concept and design. He performed experiments, data analysis, and interpretation. He drafted the manuscript and contributed to the approval of the final version of the manuscript. Matthew N. Nazzal performed experiments, data analysis, and interpretation. He drafted the manuscript and contributed to the approval of the final version of the manuscript. Liping Feng studied the concept and design. She drafted the manuscript and contributed to the approval of the final version of the manuscript. Irina A. Buhimschi studied the concept and design. She drafted the manuscript and contributed to the approval of the final version of the manuscript. Amy P. Murtha studied the concept and design. She drafted the manuscript and contributed to the approval of the final version of the manuscript.

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Allen, T.K., Nazzal, M.N., Feng, L. et al. Progestins Inhibit Tumor Necrosis Factor α—Induced Matrix Metalloproteinase 9 Activity via the Glucocorticoid Receptor in Primary Amnion Epithelial Cells. Reprod. Sci. 26, 1193–1202 (2019). https://doi.org/10.1177/1933719118811646

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