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The impact of 17β-estradiol and progesterone therapy on peripheral blood mononuclear cells of asthmatic patients

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Abstract

There is a significant fluctuation in clinical symptoms of asthmatic females during their life course, suggesting that the reproductive status and the level of sex hormones may affect the development of asthma and its exacerbation. In this study, we aimed to assess the biological effects of 17β-estradiol (E2) and progesterone (P4), alone or in combination form, on the transcription factors and production of cytokines in peripheral blood mononuclear cells (PBMCs). PBMCs of the mild-to-moderate asthmatic patients and healthy controls (HCs) were treated with equivalent serum levels of E2 or P4 maintained during hormone replacement therapy (HRT). The expression levels of T-bet, GATA-3, RORγt, PU.1, and Foxp3 were assessed by quantitative PCR. We also measured the concentration of IL-4, IL-9, IL-10, IFN-γ, and TGF-β in cell culture supernatants using ELISA. IL-4 production and GATA-3 expression levels slightly increased when asthmatic PBMCs were treated with E2 (p < 0.01), P4 (p < 0.01), or E2 + P4 (p < 0.001) compared to the untreated cells. IL-9 secretion (p < 0.001) and PU.1 gene expression levels (p < 0.05) were slightly higher in asthmatic patients’ PBMCs before treatment but hormone therapy did not affect the level of them. Although the untreated asthmatic PBMCs produced a lower amount of IFN-γ compared to HCs (p < 0.01), hormone treatment did not affect the levels of IFN-γ secretion in patient groups. Moreover, we did not observe any significant changes in IL-10 and TGF-β secretion in the supernatant of hormone treated cells. We found that the common applied HRT may faintly increase GATA-3 expression and IL-4 production levels in PBMCs of asthmatic patients and can slightly increase asthma severity.

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Abbreviations

E2:

17β-Estradiol

ER:

Estrogen receptor

ELISA:

Enzyme‐linked immunosorbent assay

ELISpot:

Enzyme-linked immune absorbent spot

GINA:

Global initiative for asthma

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

HC:

Healthy control

HRT:

Hormone replacement therapy

IL:

Interleukin

ILC:

Innate lymphoid cell

IFN-γ:

Interferon gamma

ICAM-1:

Intracellular cell adhesion molecule-1

IQR:

Interquartile range

P4:

Progesterone

PBMCs:

Peripheral blood mononuclear cells

PIBF:

Progesterone-induced blocking factor

RT:

Room temperature

RQ:

Relative quantity

TH :

T helper

TMB:

Tetramethylbenzidine

TGF-β:

Transforming growth factor beta

Treg :

Regulatory T helper cell

References

  1. Hamilton D, Lehman H (2020) Asthma phenotypes as a guide for current and future biologic therapies. Clin Rev Allergy Immunol 59(2):160–174

    CAS  PubMed  Google Scholar 

  2. Kuruvilla ME, Lee FE-H, Lee GB (2019) Understanding asthma phenotypes, endotypes, and mechanisms of disease. Clin Rev Allergy Immunol 56(2):219–233

    PubMed  PubMed Central  Google Scholar 

  3. Fazlollahi MR, Najmi M, Fallahnezhad M, Sabetkish N, Kazemnejad A, Bidad K et al (2018) The prevalence of asthma in Iranian adults: The first national survey and the most recent updates. Clin Respir J 12(5):1872–1881

    PubMed  Google Scholar 

  4. Moorman JE, Zahran H, Truman BI, Molla MT (2011) Control Cfd, Prevention. Current asthma prevalence-United States, 2006–2008. MMWR Surveill Summ 60(Suppl):84–86

    Google Scholar 

  5. Wegmann M (2009) Th2 cells as targets for therapeutic intervention in allergic bronchial asthma. Expert Rev Mol Diagn 9(1):85–100

    CAS  PubMed  Google Scholar 

  6. Wenzel S, Wilbraham D, Fuller R, Getz EB, Longphre M (2007) Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet 370(9596):1422–1431

    CAS  PubMed  Google Scholar 

  7. Hayashi N, Yoshimoto T, Izuhara K, Matsui K, Tanaka T, Nakanishi K (2007) T helper 1 cells stimulated with ovalbumin and IL-18 induce airway hyperresponsiveness and lung fibrosis by IFN-γ and IL-13 production. Proc Natl Acad Sci 104(37):14765–14770

    CAS  PubMed  Google Scholar 

  8. Sugimoto T, Ishikawa Y, Yoshimoto T, Hayashi N, Fujimoto J, Nakanishi K (2004) Interleukin 18 acts on memory T helper cells type 1 to induce airway inflammation and hyperresponsiveness in a naive host mouse. J Exp Med 199(4):535–545

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Bettelli E, Korn T, Oukka M, Kuchroo VK (2008) Induction and effector functions of T H 17 cells. Nature 453(7198):1051

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Nakae S, Komiyama Y, Nambu A, Sudo K, Iwase M, Homma I et al (2002) Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses. Immunity 17(3):375–387

    CAS  PubMed  Google Scholar 

  11. Real FG, Svanes C, Björnsson EH, Franklin K, Gislason D, Gislason T et al (2006) Hormone replacement therapy, body mass index and asthma in perimenopausal women: a cross sectional survey. Thorax 61(1):34–40

    Google Scholar 

  12. Barr RG, Wentowski CC, Grodstein F, Somers SC, Stampfer MJ, Schwartz J et al (2004) Prospective study of postmenopausal hormone use and newly diagnosed asthma and chronic obstructive pulmonary disease. Arch Intern Med 164(4):379–386

    PubMed  Google Scholar 

  13. Hepburn MJ, Dooley DP, Morris MJ (2001) The effects of estrogen replacement therapy on airway function in postmenopausal, asthmatic women. Arch Intern Med 161(22):2717–2720

    CAS  PubMed  Google Scholar 

  14. Townsend EA, Meuchel LW, Thompson MA, Pabelick CM, Prakash Y (2011) Estrogen increases nitric-oxide production in human bronchial epithelium. J Pharmacol Exp Ther 339(3):815–824

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Global Initiative for Asthma (GINA) Global strategy for asthma management and prevention, 2017. https://www.ginasthma.org

  16. Endrikat J, Blode H, Gerlinger C, Rosenbaum P, Kuhnz W (2002) A pharmacokinetic study with a low-dose oral contraceptive containing 20 μg ethinylestradiol plus 100 μg levonorgestrel. Eur J Contracept Reprod Health Care 7(2):79–90

    CAS  PubMed  Google Scholar 

  17. Marks MA, Gravitt PE, Burk RD, Studentsov Y, Farzadegan H, Klein SL (2010) Progesterone and 17β-estradiol enhance regulatory responses to human papillomavirus type 16 virus-like particles in peripheral blood mononuclear cells from healthy women. Clin Vaccine Immunol 17(4):609–617

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Rao CK, Moore CG, Bleecker E, Busse WW, Calhoun W, Castro M et al (2013) Characteristics of perimenstrual asthma and its relation to asthma severity and control: data from the Severe Asthma Research Program. Chest 143(4):984–992

    PubMed  Google Scholar 

  19. Kos-Kudła B, Ostrowska Z, Marek B, Ciesielska-Kopacz N, Sieminska L, Kajdaniuk D et al (2000) Hormone replacement therapy in postmenopausal asthmatic women. J Clin Pharm Ther 25(6):461–466

    PubMed  Google Scholar 

  20. Engelmann F, Rivera A, Park B, Messerle-Forbes M, Jensen JT, Messaoudi I (2016) Impact of estrogen therapy on lymphocyte homeostasis and the response to seasonal influenza vaccine in post-menopausal women. PLoS ONE 11(2):e0149045

    PubMed  PubMed Central  Google Scholar 

  21. Jenkins M, Dharmage S, Flander L, Douglass J, Ugoni A, Carlin J et al (2006) Parity and decreased use of oral contraceptives as predictors of asthma in young women. Clin Exp Allergy 36(5):609–613

    CAS  PubMed  Google Scholar 

  22. Nwaru BI, Sheikh A (2015) Hormonal contraceptives and asthma in women of reproductive age: analysis of data from serial national Scottish Health Surveys. J R Soc Med 108(9):358–371

    PubMed  PubMed Central  Google Scholar 

  23. Macsali F, Real FG, Omenaas ER, Bjorge L, Janson C, Franklin K et al (2009) Oral contraception, body mass index, and asthma: a cross-sectional Nordic-Baltic population survey. J Allergy Clin Immunol 123(2):391–397

    PubMed  Google Scholar 

  24. Salam MT, Wenten M, Gilliland FD (2006) Endogenous and exogenous sex steroid hormones and asthma and wheeze in young women. J Allergy Clin Immunol 117(5):1001–1007

    CAS  PubMed  Google Scholar 

  25. Burleson MH, Malarkey WB, Cacioppo JT, Poehlmann KM, Kiecolt-Glaser JK, Berntson GG et al (1998) Postmenopausal hormone replacement: effects on autonomic, neuroendocrine, and immune reactivity to brief psychological stressors. Psychosom Med 60(1):17–25

    CAS  PubMed  Google Scholar 

  26. Yang J-H, Chen C-D, Wu M-Y, Chao K-H, Yang Y-S, Ho H-N (2000) Hormone replacement therapy reverses the decrease in natural killer cytotoxicity but does not reverse the decreases in the T-cell subpopulation or interferon-gamma production in postmenopausal women. Fertil Steril 74(2):261–267

    CAS  PubMed  Google Scholar 

  27. Bonds RS, Midoro-Horiuti T (2013) Estrogen effects in allergy and asthma. Curr Opin Allergy Clin Immunol 13(1):92

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Cai Y, Zhou J, Webb DC (2012) Estrogen stimulates Th2 cytokine production and regulates the compartmentalisation of eosinophils during allergen challenge in a mouse model of asthma. Int Arch Allergy Immunol 158(3):252–260

    CAS  PubMed  Google Scholar 

  29. Broide DH (2008) Immunologic and inflammatory mechanisms that drive asthma progression to remodeling. J Allergy Clin Immunol 121(3):560–570

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Baldaçara RPDC, Silva I (2017) Association between asthma and female sex hormones. Sao Paulo Med J 135(1):4–14

    PubMed  Google Scholar 

  31. Haghmorad D, Salehipour Z, Nosratabadi R, Rastin M, Kokhaei P, Mahmoudi MB et al (2016) Medium-dose estrogen ameliorates experimental autoimmune encephalomyelitis in ovariectomized mice. J Immunotoxicol 13(6):885–896

    CAS  PubMed  Google Scholar 

  32. Kanda N, Hoashi T, Saeki H (2019) The roles of sex hormones in the course of atopic dermatitis. Int J Mol Sci 20(19):4660

    CAS  PubMed Central  Google Scholar 

  33. Vock C, Hauber H-P, Wegmann M (2010) The other T helper cells in asthma pathogenesis. J Allergy 2010:519298

    Google Scholar 

  34. Wang W, Cheng ZS, Chen YF, Lin YH (2016) Increased circulating IL-9-producing CD8+ T cells are associated with eosinophilia and high FeNO in allergic asthmatics. Exp Ther Med 12(6):4055–4060

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Sehra S, Yao W, Nguyen ET, Glosson-Byers NL, Akhtar N, Zhou B et al (2015) TH9 cells are required for tissue mast cell accumulation during allergic inflammation. J Allergy Clin Immunol 136(2):433–440

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Turner H, Kinet J-P (1999) Signalling through the high-affinity IgE receptor FcεRI. Nature 402(suppl 6760):24

    Google Scholar 

  37. Petit-Frere C, Dugas B, Braquet P, Mencia-Huerta J (1993) Interleukin-9 potentiates the interleukin-4-induced IgE and IgG1 release from murine B lymphocytes. Immunology 79(1):146

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Koch S, Sopel N, Finotto S (2017) Th9 and other IL-9-producing cells in allergic asthma. Seminars in immunopathology. Springer, Berlin

    Google Scholar 

  39. Maggi E, Parronchi P, Manetti R, Simonelli C, Piccinni M, Rugiu FS et al (1992) Reciprocal regulatory effects of IFN-gamma and IL-4 on the in vitro development of human Th1 and Th2 clones. J Immunol 148(7):2142–2147

    CAS  PubMed  Google Scholar 

  40. Look DC, Rapp SR, Keller BT, Holtzman MJ (1992) Selective induction of intercellular adhesion molecule-1 by interferon-gamma in human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 263(1):L79–L87

    CAS  Google Scholar 

  41. Campbell D, Fryga A, Bol S, Kemp A (1999) Intracellular interferon-gamma (IFN-γ) production in normal children and children with atopic dermatitis. Clin Exp Immunol 115(3):377

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Kimura M, Yamaide A, Tsuruta S, Okafuji I, Yoshida T (2002) Development of the capacity of peripheral blood mononuclear cells to produce IL-4, IL-5 and IFN-γ upon stimulation with house dust mite in children with atopic dermatitis. Int Arch Allergy Immunol 127(3):191–197

    CAS  PubMed  Google Scholar 

  43. El-Mezzein R, Matsumoto T, Nomiyama H, Miike T (2001) Increased secretion of IL-18 in vitro by peripheral blood mononuclear cells of patients with bronchial asthma and atopic dermatitis. Clin Exp Immunol 126(2):193–198

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Jung T, Witzak K, Dieckhoff K, Zachmann K, Heidrich S, Aversa G et al (1999) IFN-gamma is only partially restored by co-stimulation with IL-12, IL-2, IL-15, IL-18 or engagement of CD28. Clin Exp Allergy 29(2):207–216

    CAS  PubMed  Google Scholar 

  45. Yao Y, Li H, Ding J, Xia Y, Wang L (2017) Progesterone impairs antigen-non-specific immune protection by CD8 T memory cells via interferon-γ gene hypermethylation. PLoS Pathog 13(11):e1006736

    PubMed  PubMed Central  Google Scholar 

  46. Matalka KZ (2003) Riginal AR. Neuroendocrinol Lett 24(3/4):185–191

    CAS  PubMed  Google Scholar 

  47. Xiang Y, Jin Q, Li L, Yang Y, Zhang H, Liu M et al (2018) Physiological low-dose oestrogen promotes the development of experimental autoimmune thyroiditis through the up-regulation of Th1/Th17 responses. J Reprod Immunol 126:23–31

    CAS  PubMed  Google Scholar 

  48. Al-Ramli W, Préfontaine D, Chouiali F, Martin JG, Olivenstein R, Lemière C et al (2009) TH17-associated cytokines (IL-17A and IL-17F) in severe asthma. J Allergy Clin Immunol 123(5):1185–1187

    CAS  PubMed  Google Scholar 

  49. Newcomb DC, Cephus JY, Boswell MG, Fahrenholz JM, Langley EW, Feldman AS et al (2015) Estrogen and progesterone decrease let-7f microRNA expression and increase IL-23/IL-23 receptor signaling and IL-17A production in patients with severe asthma. J Allergy Clin Immunol 136(4):1025–1034

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Vélez-Ortega AC, Temprano J, Reneer MC, Ellis GI, McCool A, Gardner T et al (2013) Enhanced generation of suppressor T cells in patients with asthma taking oral contraceptives. J Asthma 50(3):223–230

    PubMed  PubMed Central  Google Scholar 

  51. Adurthi S, Kumar MM, Vinodkumar H, Mukherjee G, Krishnamurthy H, Acharya KK et al (2017) Oestrogen receptor-α binds the FOXP3 promoter and modulates regulatory T-cell function in human cervical cancer. Sci Rep 7(1):17289

    PubMed  PubMed Central  Google Scholar 

  52. Iannello A, Rolla S, Maglione A, Ferrero G, Bardina V, Inaudi I et al (2018) Pregnancy epigenetic signature in T helper 17 and T regulatory cells in multiple sclerosis. Front Immunol 9:3075

    CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to express our sincere thanks to all volunteers who participated in this study and donated blood samples.

Funding

This study was supported by Grants # 26562 and 26572 from Iran University of Medical Sciences.

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Authors and Affiliations

  1. Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

    Leila Nejatbakhsh Samimi, Majid Khoshmirsafa, Paria Bayati & Reza Falak

  2. Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran

    Leila Nejatbakhsh Samimi, Majid Khoshmirsafa, Paria Bayati & Reza Falak

  3. Department of Allergy and Clinical Immunology, Rasul-E-Akram Hospital, Iran University of Medical Sciences, Tehran, Iran

    Morteza Fallahpour

  4. Air Pollution Research Center, Iran University of Medical Sciences, Tehran, Iran

    Seyed Ali Javad Moosavi

  5. Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran

    Rasoul Baharlou

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  1. Leila Nejatbakhsh Samimi
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Contributions

RB and PB introduced the initial concept, LNS, SAJM and RF designed the project; MF and SAJM introduced the participants including the patients and controls from the clinic; LNS, MK and RF performed the initial experiments and optimized the methods; LNS fulfilled the main experiments; LNS, MF, MK collected data and performed statistical analysis, LNS, RF, SAJM and MK interpreted the findings; LNS wrote the manuscript draft; RF and MK critically reviewed and revised the final draft. All authors have read and approved the manuscript.

Corresponding author

Correspondence to Reza Falak.

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Conflict of interest

The authors declares that they have no conflict of interest.

Ethical approval

All subjects gave written consent and the study was approved by the Ethics Committee of Iran University of Medical Sciences (IRIUMS. REC 1398. 9311127007). All experiments were performed in compliance with the Declaration of Helsinki.

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Nejatbakhsh Samimi, L., Fallahpour, M., Khoshmirsafa, M. et al. The impact of 17β-estradiol and progesterone therapy on peripheral blood mononuclear cells of asthmatic patients. Mol Biol Rep 48, 297–306 (2021). https://doi.org/10.1007/s11033-020-06046-6

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