Progesterone-induced blocking factor (PIBF) influences the expression of membrane progesterone receptors (mPRs) on peripheral CD4+ T lymphocyte cells in normal fertile females

Abstract

Purpose

Progesterone-induced blocking factor (PIBF) is a protein secreted by lymphocytes exposed to progesterone (P4). P4 and PIBF have immunomodulatory effects on peripheral CD4+ T cells during normal pregnancy. Membrane progesterone receptors (mPRs) may correlate with the immunomodulatory properties of P4 on T cells. Variation in expression of mPRs may influence P4 regulatory performance during pregnancy. On the other hand, PIBF increases in pregnant normal women compared to women who have experienced abortion. The present study aimed to determine whether PIBF, in addition to having a direct influence on the immune system, can affect P4 performance through its effect on mPR expression. Such novel research findings demonstrate the importance of PIBF in the maintenance of pregnancy.

Methods

Isolated peripheral blood mononuclear cells (PBMCs) from 30 healthy women were stimulated with the mitogen phytohemagglutinin (PHA). Cells were either exposed to various concentrations of PIBF or had no exposure at all in a culture medium at 37 °C for 3 days. The mean fluorescence intensity (MFI) of mPRα and mPRβ was evaluated using polyclonal and monoclonal antibodies on CD4+ T cells.

Results

PIBF was able to significantly increase mPR expression on the surface of peripheral CD4+ T cells (p ≤ 0.05).

Conclusion

This study characterized the effects of PIBF on mPR expression on peripheral CD4+ T cells of healthy fertile women. Thus, a decrease in PIBF concentration during abnormal pregnancy can modulate mPR expression and regulatory performance of P4 on T cells. Future research into this issue is likely to open up a new understanding of the etiology of abortion.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

Abbreviations

P4:

Progesterone

PIBF:

Progesterone-induced blocking factor

PR:

Progesterone receptor

mPRs:

Membrane progesterone receptors

PHA:

Phytohemagglutinin

PBS:

Phosphate-buffered saline

PBMCs:

Peripheral blood mononuclear cells

References

  1. 1.

    Backstrom CT et al (1982) Pulsatile secretion of LH, FSH, prolactin, oestradiol and progesterone during the human menstrual cycle. Clin Endocrinol (Oxf) 17(1):29–42

    CAS  Article  Google Scholar 

  2. 2.

    Mihm M, Gangooly S, Muttukrishna S (2011) The normal menstrual cycle in women. Anim Reprod Sci 124(3–4):229–236

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Lissauer D et al (2015) Progesterone promotes maternal-fetal tolerance by reducing human maternal T-cell polyfunctionality and inducing a specific cytokine profile. Eur J Immunol 45(10):2858–2872

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Nadeem L et al (2016) Molecular evidence of functional progesterone withdrawal in human myometrium. Nat Commun 7:11565

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Shah NM, Imami N, Johnson MR (2018) Progesterone modulation of pregnancy-related immune responses. Front Immunol 9:1293

    PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Arruvito L et al (2008) NK cells expressing a progesterone receptor are susceptible to progesterone-induced apoptosis. J Immunol 180(8):5746–5753

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Younglai EV et al (2006) Binding of progesterone to cell surfaces of human granulosa-lutein cells. J Steroid Biochem Mol Biol 101(1):61–67

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Behera MA et al (2009) Progesterone stimulates mitochondrial activity with subsequent inhibition of apoptosis in MCF-10A benign breast epithelial cells. Am J Physiol Endocrinol Metab 297(5):E1089–E1096

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Patel B et al (2015) Role of nuclear progesterone receptor isoforms in uterine pathophysiology. Hum Reprod Update 21(2):155–173

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Miyaura H, Iwata M (2002) Direct and indirect inhibition of Th1 development by progesterone and glucocorticoids. J Immunol 168(3):1087–1094

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Areia A et al (2015) Membrane progesterone receptors in human regulatory T cells: a reality in pregnancy. BJOG 122(11):1544–1550

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Szekeres-Bartho J et al (1990) Reactivity of lymphocytes to a progesterone receptor-specific monoclonal antibody. Cell Immunol 125(2):273–283

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Mansour I, Reznikoff-Etievant MF, Netter A (1994) No evidence for the expression of the progesterone receptor on peripheral blood lymphocytes during pregnancy. Hum Reprod 9(8):1546–1549

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Bamberger CM et al (1999) Dissociative glucocorticoid activity of medroxyprogesterone acetate in normal human lymphocytes. J Clin Endocrinol Metab 84(11):4055–4061

    CAS  PubMed  Google Scholar 

  15. 15.

    Dosiou C et al (2008) Expression of membrane progesterone receptors on human T lymphocytes and Jurkat cells and activation of G-proteins by progesterone. J Endocrinol 196(1):67–77

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Szekeres-Bartho J et al (1985) The mechanism of the inhibitory effect of progesterone on lymphocyte cytotoxicity: I. Progesterone-treated lymphocytes release a substance inhibiting cytotoxicity and prostaglandin synthesis. Am J ReprodImmunolMicrobiol 9(1):15–18

    CAS  Google Scholar 

  17. 17.

    Cohen RA, Check JH, Dougherty MP (2016) Evidence that exposure to progesterone alone is a sufficient stimulus to cause a precipitous rise in the immunomodulatory protein the progesterone induced blocking factor (PIBF). J Assist Reprod Genet 33(2):221–229

    PubMed  Article  Google Scholar 

  18. 18.

    Raghupathy R et al (2009) Progesterone-induced blocking factor (PIBF) modulates cytokine production by lymphocytes from women with recurrent miscarriage or preterm delivery. J Reprod Immunol 80(1–2):91–99

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Faust Z et al (1999) Progesterone-induced blocking factor inhibits degranulation of natural killer cells. Am J Reprod Immunol 42(2):71–75

    CAS  PubMed  Google Scholar 

  20. 20.

    Hudic I, Fatusic Z (2009) Progesterone-induced blocking factor (PIBF) and Th(1)/Th(2) cytokine in women with threatened spontaneous abortion. J Perinat Med 37(4):338–342

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Wu S et al (2014) Expression of kisspeptin/GPR54 and PIBF/PR in the first trimester trophoblast and decidua of women with recurrent spontaneous abortion. Pathol Res Pract 210(1):47–54

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Hudic I et al (2016) Lower urinary and serum progesterone-induced blocking factor in women with preterm birth. J Reprod Immunol 117:66–69

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Wegmann TG et al (1993) Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today 14(7):353–356

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Hsi BL, Hunt JS, Atkinson JP (1991) Differential expression of complement regulatory proteins on subpopulations of human trophoblast cells. J Reprod Immunol 19(3):209–223

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Aluvihare VR, Kallikourdis M, Betz AG (2004) Regulatory T cells mediate maternal tolerance to the fetus. Nat Immunol 5(3):266–271

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    King A et al (2000) Surface expression of HLA-C antigen by human extravillous trophoblast. Placenta 21(4):376–387

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Munn DH et al (1998) Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281(5380):1191–1193

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Makhseed M et al (2001) Th1 and Th2 cytokine profiles in recurrent aborters with successful pregnancy and with subsequent abortions. Hum Reprod 16(10):2219–2226

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Piccinni MP et al (1995) Progesterone favors the development of human T helper cells producing Th2-type cytokines and promotes both IL-4 production and membrane CD30 expression in established Th1 cell clones. J Immunol 155(1):128–133

    CAS  PubMed  Google Scholar 

  30. 30.

    Weinberg A et al (2011) Effect of menstrual cycle variation in female sex hormones on cellular immunity and regulation. J Reprod Immunol 89(1):70–77

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Lee JH et al (2011) Progesterone promotes differentiation of human cord blood fetal T cells into T regulatory cells but suppresses their differentiation into Th17 cells. J Immunol 187(4):1778–1787

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Chien EJ et al (2007) The non-genomic effects on Na+/H+-exchange 1 by progesterone and 20alpha-hydroxyprogesterone in human T cells. J Cell Physiol 211(2):544–550

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Areia A et al (2016) Can membrane progesterone receptor alpha on T regulatory cells explain the ensuing human labour? J Reprod Immunol 113:22–26

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Szekeres-Bartho J et al (1989) Lymphocytic progesterone receptors in normal and pathological human pregnancy. J Reprod Immunol 16(3):239–247

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Chiu L et al (1996) Enhancement of the expression of progesterone receptor on progesterone-treated lymphocytes after immunotherapy in unexplained recurrent spontaneous abortion. Am J Reprod Immunol 35(6):552–557

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Rafiee M et al (2019) Vitamin D3 induces the expression of membrane progesterone receptors (mPRs) on naive CD4+ T lymphocyte cells in women of reproductive age. Int Immunopharmacol 72:55–61

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Polgar B et al (2004) Urinary progesterone-induced blocking factor concentration is related to pregnancy outcome. Biol Reprod 71(5):1699–1705

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Kozma N et al (2006) Progesterone-induced blocking factor activates STAT6 via binding to a novel IL-4 receptor. J Immunol 176(2):819–826

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgments

The authors gratefully acknowledge the financial support of Isfahan University of Medical Sciences and Birjand University of Medical Sciences.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Mohsen Naseri.

Ethics declarations

Ethical approval

This study was approved by the Institutional Ethics Committee of Isfahan University of Medical Science (code of ethics: 1,395,030,632).

Informed consent

Written informed consent was obtained from all patients participating in this study.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Dr Mitra Rafiee is the first author.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Rafiee, M., Rezaei, A., Alipour, R. et al. Progesterone-induced blocking factor (PIBF) influences the expression of membrane progesterone receptors (mPRs) on peripheral CD4+ T lymphocyte cells in normal fertile females. Hormones (2021). https://doi.org/10.1007/s42000-021-00291-5

Download citation

Keywords

  • Progesterone (P4)
  • Progesterone-induced blocking factor (PIBF)
  • Membrane progesterone receptor α and β
  • CD4+ T lymphocyte cells