Skip to main content

Advertisement

SpringerLink
Log in

Progesterone Receptor Membrane Component 1 as the Mediator of the Inhibitory Effect of Progestins on Cytokine-Induced Matrix Metalloproteinase 9 Activity In Vitro

  • Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Progesterone (P4) and the progestin, 17α-hydroxyprogesterone caproate, are clinically used to prevent preterm births (PTBs); however, their mechanism of action remains unclear. Cytokine-induced matrix metalloproteinase 9 (MMP-9) activity plays a key role in preterm premature rupture of the membranes and PTB. We demonstrated that the primary chorion cells and the HTR8/SVneo cells (cytotrophoblast cell line) do not express the classical progesterone receptor (PGR) but instead a novel progesterone receptor, progesterone receptor membrane component 1 (PGRMC1), whose role remains unclear. Using HTR8/SVneo cells in culture, we further demonstrated that 6 hours pretreatment with medroxyprogesterone acetate (MPA) and dexamethasone (Dex) but not P4 or 17α-hydroxyprogesterone hexanoate significantly attenuated tumor necrosis factor α-induced MMP-9 activity after a 24-hour incubation period. The inhibitory effect of MPA, but not Dex, was attenuated when PGRMC1 expression was successfully reduced by PGRMC1 small interfering RNA. Our findings highlight a possible novel role of PGRMC1 in mediating the effects of MPA and in modulating cytokine-induced MMP-9 activity in cytotrophoblast cells in vitro.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet. 2008;371(9606):75–84.

    Article  Google Scholar 

  2. George RB, Kalich J, Yonish B, Murtha AP. Apoptosis in the chorion of fetal membrane s in preterm premature rupture of membranes. Am J Perinatol. 2008;25(1):29–32.

    Article  Google Scholar 

  3. Fortunato SJ, Menon R, Lombardi SJ. Amniochorion gelatinase–gelatinase inhibitor imbalance in vitro: a possible infectious pathway to rupture. Obstet Gynecol. 2000;95(2):240–244.

    CAS  PubMed  Google Scholar 

  4. Fortunato SJ, Menon R, Lombardi SJ. Role of tumor necrosis factor α in the premature rupture of membranes and preterm labor pathways. Am J Obstet Gynecol. 2002;187(5):1159–1162.

    Article  CAS  Google Scholar 

  5. 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  Google Scholar 

  6. 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(3):1353–1361.

    Article  CAS  Google Scholar 

  7. 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  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  10. 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 Metabol. 2008;93(1):252–259.

    Article  CAS  Google Scholar 

  11. Murtha AP, Feng L, Yonish B, Leppert PC, Schomberg DW. Progesterone protects fetal chorion and maternal decidua cells from calcium-induced death. Am J Obstet Gynecol. 2007;196(3): e251–e257.

    Article  Google Scholar 

  12. 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  Google Scholar 

  13. Goldman S, Weiss A, Almalah I, Shalev E. Progesterone receptor expression in human decidua and fetal membranes before and after contractions: possible mechanism for functional progesterone withdrawal. Mol Hum Reprod. 2005;11(4):269–277.

    Article  CAS  Google Scholar 

  14. Chappell PE, Lydon JP, Conneely OM, O’Malley BW, Levine JE. Endocrine defects in mice carrying a null mutation for the progesterone receptor gene. Endocrinology. 1997;138(10):4147–4152.

    Article  CAS  Google Scholar 

  15. Peluso JJ. Non-genomic actions of progesterone in the normal and neoplastic mammalian ovary. Semin Reprod Med. 2007;25(3): 198–207.

    Article  CAS  Google Scholar 

  16. Falkenstein E, Schmeiding K, Lange A, et al. Localization of a putative progesterone membrane binding protein in porcine hepatocytes. Cell Mol Biol (Noisy-le-grand). 1998;44(4):571–578.

    CAS  Google Scholar 

  17. Peluso JJ, Romak J, Liu X. Progesterone receptor membrane component-1 (PGRMC1) is the mediator of progesterone’s antia-poptotic 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  Google Scholar 

  18. Graham CH, Hawley TS, Hawley RC, et al. Establishment and characterization of first trimester human trophoblast cells with extended lifespan. Exp Cell Res. 1993;206(2):204–211.

    Article  CAS  Google Scholar 

  19. 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  Google Scholar 

  20. Li W, Li H, Bocking AD, Challis JR. Tumor necrosis factor stimulates matrix metalloproteinase 9 secretion from cultured human chorionic trophoblast cells through TNF receptor 1 signaling to IKBKB-NFKB and MAPK1/3 pathway. Biol Reprod. 2010; 83(3):481–487.

    Article  CAS  Google Scholar 

  21. 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  Google Scholar 

  22. Kilburn BA, Wang J, Duniec-Dmuchkowski ZM, Leach RE, Romero R, Armant DR. Extracellular matrix composition and hypoxia regulate the expression of HLA-G and Integrins in a human trophoblast cell line. Biol Reprod. 2000;62(3):739–747.

    Article  CAS  Google Scholar 

  23. Moore RM, Schatz F, Kumar D, et al. Alpha-lipoic acid inhibits thrombin-induced fetal membrane weakening in vitro. Placenta. 2010;31(10):886–892.

    Article  CAS  Google Scholar 

  24. Peluso JJ, DeCerbo J, Lodde V. Evidence for a genomic mechanism of action for progesterone receptor membrane component-1. Steroids. 2012;77(10): 1007–1012.

    Article  CAS  Google Scholar 

  25. Arici A, Marshburn PB, MacDonald PC, Dombrowski RA. Progesterone metabolism in human endometrial stromal and gland cells in culture. Steroids. 1999;64(8):530–534.

    Article  CAS  Google Scholar 

  26. Manuck TA, Lai Y, Meis PJ, et al. Progesterone receptor polymorphisms and clinical response to 17-alpha-hydroxyprogesterone caproate. Am J Obstet Gynecol. 2011;205(2):135.e1–135.e9.

    Article  Google Scholar 

  27. Stopińska-Gluszak U, Waligóra J, Grzela T, et al. Effect of estrogen/progesterone hormone replacement therapy on natural killer cell cytotoxicity and immunoregulatory cytokine release by peripheral blood mononuclear cells of postmenopausal women. J Reprod Immunol. 2006;69(1):65–75.

    Article  Google Scholar 

  28. Sitruk-Ware R. New progestagens for contraceptive use. Human Reprod Update. 2006;12(2):169–178.

    Article  CAS  Google Scholar 

  29. Kontula K, Paavonen T, Luukkainen T, Andersson LC. Binding of progestins to the glucocorticoid receptor: correlation to their glucocorticoid-like effects on in vitro functions of human mononuclear leukocytes. Biochem Pharmacol. 1983;32(9):1511–1518.

    Article  CAS  Google Scholar 

  30. Beppu M, Ikebe T, Shirasuna K. The inhibitory effects of immunosuppressive factors, dexamethasone and interleukin-4, on NF-κB-mediated protease production by oral cancer. Biochim Bio-phys Acta. 2002;1586(1):11–22.

    Article  CAS  Google Scholar 

  31. Ruan X, Neubauer H, Yang Y, et al. Progestogens and membrane-initiated effects on the proliferation of human breast cancer cells. Climacteric. 2012;15(5):467–72.

    Article  CAS  Google Scholar 

  32. Neubauer H, Yang Y, Seeger H, et al. The presence of a membrane-bound progesterone receptor sensitizes the estradiol-induced effect on the proliferation of human breast cancer cells. Menopause. 2011;18(8):845–850.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

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

    Terrence K. Allen MBBS, FRCA

  2. Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Duke University School of Medicine, Durham, NC, USA

    Liping Feng MD, Chad A. Grotegut MD & Amy P. Murtha MD

Authors
  1. Terrence K. Allen MBBS, FRCA
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Liping Feng MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chad A. Grotegut MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amy P. Murtha MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Terrence K. Allen MBBS, FRCA.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Allen, T.K., Feng, L., Grotegut, C.A. et al. 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. 21, 260–268 (2014). https://doi.org/10.1177/1933719113493514

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719113493514

Keywords

Search

Navigation