Endometrial Cytokines in Women with Reproductive Disorders

Irina N. Danusevich, Lyudmila M. Lazareva, Uliana M. Nemchenko, Lyubov I. Kolesnikova

 
International Journal of Biomedicine. 2021;11(4):526-531.
DOI: 10.21103/Article11(4)_OA20
Originally published December 10, 2021

Abstract: 

The purpose of this research was to study changes in endometrial cytokine concentrations in women suffering from reproductive disorders with and without chronic endometritis (CE) to justify pathogenetic treatment.
Methods and Results: The study included 100 women of reproductive age with reproductive disorders. Group 1 included 50 patients with reproductive disorders and CE; Group 2 included 50 patients with reproductive disorders and without CE. Later on, all patients were divided into the following subgroups: Sub1A (n=31), and Sub2A (n=16) with an isolated bacterial flora, Sub1B (n=19) and Sub2B (n=34) with the absence of bacterial flora. The control group consisted of 31 fertile women.
Endometrial aspiration pipe biopsy was performed on days 4-9 of the menstrual cycle (middle proliferative phase) using a disposable intrauterine probe (Taizhou Kechuang Medical Apparatus Co., Ltd, China) followed by histological examination of endometrial tissue. Laboratory diagnostics for sexually transmitted infections (STIs) was performed using the bacterial culture method. For the diagnosis of viral infection (HPV, HSV, CMV), cervical samples were studied using PCR. If STIs were detected, the patients were excluded from further research. Ultrasound examination of the pelvic organs was performed using the Aloka-5500 device with a 7MHz vaginal probe in two-dimensional visualization mode. The concentration of cytokines (IL-1β, INF-γ, TNF-α, ILs-4,6,8,10) in the endometrium was determined using the Protein Contour test systems (Saint Petersburg) and Multiskan EX ELISA Analyzer (Germany).
In both groups, reproductive disorders were accompanied by hypoprogesteronemia and relative hyperestrogenemia, significantly apparent in CE. We found a 3-fold increase in the level of tissue pro- and anti-inflammatory cytokines (IL-1β, IL-4,6,10, INF-γ), and a 4-fold increase in the level of TNF-α and IL-8 in Group 1, compared to the CG. In Group 2, we found a 1.4-fold increase in the levels of IL-1β and INF-γ, compared to the CG.
In Sub 1a, the levels of IL-6 and IL-8 were significantly higher than in the control group. In Sub1A, the isolated bacterial flora caused a cytokine inflammatory response characterized by a significant increase in the concentration of INF-γ and TNF-α, compared to Sub2A and Sub2B (P<0.05). In Sub1A, we found a tendency towards a decrease in the tissue levels of IL-4 compared to Sub1B and Sub2B; the IL-10 level was significantly lower than in Sub2B (P=0.0009)
Conclusion: The results obtained in the present study showed the peculiarities of changes in cytokines at the level of endometrial tissue both in chronic inflammation of the endometrium and in its absence in women with reproductive disorders. The severity of the immune response is significantly higher in patients with CE, with the most significant change in the role of IL-10.

Keywords: 
reproductive disorders • chronic endometritis • cytokines • endometrium
References: 
  1. Kolesnikova LI, Darenskaya MA, Grebenkina LA, Labygina AV, Suturina LV, Dolgikh MI, Shiphineeva TI, Darzhaev ZY, Tsyrenov TB, Rinchindorzhieva MP. Activity of lipid peroxidation in infertile women from different populations. Bull Exp Biol Med. 2012 Dec;154(2):203-5. doi: 10.1007/s10517-012-1912-4. 
  2. Michels TC. Chronic endometritis. Am Fam Physician. 1995 Jul;52(1):217-22. 
  3. Pellati D, Mylonakis I, Bertoloni G, Fiore C, Andrisani A, Ambrosini G, Armanini D. Genital tract infections and infertility. Eur J Obstet Gynecol Reprod Biol. 2008 Sep;140(1):3-11. doi: 10.1016/j.ejogrb.2008.03.009
  4. Kolesnikova LI, Kolesnikov SI, Darenskaya MA, Grebenkina LA, Nikitina OA, Lazareva LM, Suturina LV, Danusevich IN, Druzhinina EB, Semendyaev AA. Activity of LPO Processes in Women with Polycystic Ovarian Syndrome and Infertility. Bull Exp Biol Med. 2017 Jan;162(3):320-322. doi: 10.1007/s10517-017-3605-5. 
  5. Yan J, Liu C, Zhao H, Wang C, Yao H, Lu Q, Liu J, Feng Y. A cross-sectional study on the correlation between cytokines in a pelvic environment and tubal factor infertility. BMC Pregnancy Childbirth. 2020 Oct 22;20(1):644. doi: 10.1186/s12884-020-03322-y. 
  6. Gellersen B, Brosens JJ. Cyclic decidualization of the human endometrium in reproductive health and failure. Endocr Rev. 2014 Dec;35(6):851-905. doi: 10.1210/er.2014-1045.
  7. Krikun G, Trezza J, Shaw J, Rahman M, Guller S, Abrahams VM, Lockwood CJ. Lipopolysaccharide appears to activate human endometrial endothelial cells through TLR-4-dependent and TLR-4-independent mechanisms. Am J Reprod Immunol. 2012 Sep;68(3):233-7. doi: 10.1111/j.1600-0897.2012.01164.x. 
  8. Krikun G, Lockwood CJ, Abrahams VM, Mor G, Paidas M, Guller S. Expression of Toll-like receptors in the human decidua. Histol Histopathol. 2007 Aug;22(8):847-54. doi: 10.14670/HH-22.847. 
  9. Salamonsen LA, Hannan NJ, Dimitriadis E. Cytokines and chemokines during human embryo implantation: roles in implantation and early placentation. Semin Reprod Med. 2007 Nov;25(6):437-44. doi: 10.1055/s-2007-991041.
  10. Bukharin OV. [From persistence to symbiosis of microorganisms]. Journal of Microbiology, Epidemiology and Immunobiology. 2012;4:4-9. [Article in Russian].
  11. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006 Feb 24;124(4):783-801. doi: 10.1016/j.cell.2006.02.015.
  12. Beutler B. Inferences, questions and possibilities in Toll-like receptor signalling. Nature. 2004 Jul 8;430(6996):257-63. doi: 10.1038/nature02761.
  13. Urban BA, Pankov BL, Fishman EK. Postpartum complications in the abdomen and pelvis: CT evaluation. Crit Rev Diagn Imaging. 1999 Apr;40(1):1-21.
  14. Witlin AG, Sibai BM. Postpartum ovarian vein thrombosis after vaginal delivery: a report of 11 cases. Obstet Gynecol. 1995 May;85(5 Pt 1):775-80. doi: 10.1016/0029-7844(95)00040-x. 
  15. Baker JM, Chase DM, Herbst-Kralovetz MM. Uterine Microbiota: Residents, Tourists, or Invaders? Front Immunol. 2018 Mar 2;9:208. doi: 10.3389/fimmu.2018.00208. 
  16. Danusevich IN, Sharifulin EM, Nemchenko UM, Kolesnikova LI.  Member of the RAS Features of the Immune System Functioning with Persistence of Infectious Agents in Women with Chronic Endometrial Inflammation and Reproductive Disorders. International Journal of Biomedicine. 2020;10(4):362-368.
  17. Burger D, Dayer JM. Cytokines, acute-phase proteins, and hormones: IL-1 and TNF-alpha production in contact-mediated activation of monocytes by T lymphocytes. Ann N Y Acad Sci. 2002 Jun;966:464-73. doi: 10.1111/j.1749-6632.2002.tb04248.x. 
  18. Cole AM, Ganz T, Liese AM, Burdick MD, Liu L, Strieter RM. Cutting edge: IFN-inducible ELR- CXC chemokines display defensin-like antimicrobial activity. J Immunol. 2001 Jul 15;167(2):623-7. doi: 10.4049/jimmunol.167.2.623. 
  19. Couper KN, Blount DG, Riley EM. IL-10: the master regulator of immunity to infection. J Immunol. 2008 May 1;180(9):5771-7. doi: 10.4049/jimmunol.180.9.5771. 
  20. Agostinis C, Mangogna A, Bossi F, Ricci G, Kishore U, Bulla R. Uterine Immunity and Microbiota: A Shifting Paradigm. Front Immunol. 2019 Oct 17;10:2387. doi: 10.3389/fimmu.2019.02387. 
  21. Fitzgerald HC, Dhakal P, Behura SK, Schust DJ, Spencer TE. Self-renewing endometrial epithelial organoids of the human uterus. Proc Natl Acad Sci U S A. 2019 Nov 12;116(46):23132-23142. doi: 10.1073/pnas.1915389116. 
  22. Raghupathy R, Al-Mutawa E, Al-Azemi M, Makhseed M, Azizieh F, Szekeres-Bartho J. Progesterone-induced blocking factor (PIBF) modulates cytokine production by lymphocytes from women with recurrent miscarriage or preterm delivery. J Reprod Immunol. 2009 Jun;80(1-2):91-9. doi: 10.1016/j.jri.2009.01.004. 
  23. Kinsky R, Delage G, Rosin N, Thang MN, Hoffmann M, Chaouat G. A murine model of NK cell mediated resorption. Am J Reprod Immunol. 1990 Jul;23(3):73-7. doi: 10.1111/j.1600-0897.1990.tb00675.x. 
  24. Szekeres-Bartho J, Kinsky R, Chaouat G. The effect of a progesterone-induced immunologic blocking factor on NK-mediated resorption. Am J Reprod Immunol. 1990 Dec;24(4):105-7. doi: 10.1111/j.1600-0897.1990.tb01047.x.
  25. Szekeres-Bartho J, Par G, Dombay Gy, Smart YC, Volgyi Z. The antiabortive effect of progesterone-induced blocking factor in mice is manifested by modulating NK activity. Cell Immunol. 1997 May 1;177(2):194-9. doi: 10.1006/cimm.1997.1090.
  26. Danusevich I.N. Cytokine-hormonal interactions in chronic endometritis in women with reproductive disorders. Voprosy Ginekologii Akusherstva i Perinatologii. 2015;14(4):42-48. [Article in Russian].
  27. Sidelnikova V.M., Suchich G.T. Miscarriage: A Guide for Physicians. M., 2011; 546.      [Article in Russian].
  28. Kolesnikova L.I., Danusevich I.N., Kurashova N.A, Suturina L.V.,  Grebenkina L. A., Dolgikh M. I. Features of lipid peroxidation and antioxidant protection in women with chronic endometritis. Basic research. 2013; No. 9 (5): 829-832. [Article in Russian].
  29. Chiara Agostinis , Alessandro Mangogna , Fleur Bossi, Giuseppe Ricci , Uday Kishore, Roberta Bulla. Uterine Immunity and Microbiota: A Shifting Paradigm. Front Immunol. 2019; 10:2387. doi: 10.3389/fimmu.2019.02387. eCollection 2019.

Download Article
Received September 27, 2021.
Accepted October 20, 2021.
©2021 International Medical Research and Development Corporation.