Mức độ HSP70 bất thường có liên quan đến sự mất cân bằng Treg/Th17 ở bệnh nhân PCOS

Journal of Ovarian Research - Tập 14 - Trang 1-9 - 2021
Yiqing Yang1,2, Jing Xia1,2, Zhe Yang1,2, Gengxiang Wu1,2, Jing Yang1,2
1Reproductive Medical Centre, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China
2Hubei Clinical Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, People’s Republic of China

Tóm tắt

Hội chứng buồng trứng đa nang (PCOS) là một bệnh lý có viêm mãn tính không đặc hiệu mức độ thấp. Sự mất cân bằng tế bào miễn dịch tồn tại ở PCOS. Một số nghiên cứu đã tìm thấy rằng protein sốc nhiệt 70 (HSP70) có thể tham gia vào bệnh sinh miễn dịch của PCOS, nhưng mối quan hệ giữa HSP70 và tỷ lệ tế bào điều hòa T (Treg)/tế bào hỗ trợ T 17 (Th17) vẫn chưa rõ ràng. Nghiên cứu này nhằm khám phá sự tương quan giữa HSP70 và tỷ lệ Treg/Th17 và cung cấp bằng chứng về vai trò của HSP70 trong etiopathogenic miễn dịch của PCOS. Không có sự khác biệt đáng kể về tuổi tác và chỉ số khối cơ thể (BMI) giữa hai nhóm. Nồng độ estradiol cơ bản (E2) và hormone kích thích nang trứng (FSH) không cho thấy sự khác biệt đáng kể giữa hai nhóm. Nồng độ hormone hoàng thể (LH) (P < 0.01), testosterone (T) (P < 0.01), glucose (P < 0.001) và insulin (P < 0.001) ở bệnh nhân PCOS cao hơn đáng kể so với nhóm kiểm soát. Mức protein của HSP70 trong huyết thanh cao hơn đáng kể ở nhóm PCOS (P < 0.001). Tỷ lệ tế bào Treg thấp hơn đáng kể (P < 0.01), trong khi tỷ lệ tế bào Th17 của nhóm PCOS cao hơn đáng kể so với nhóm kiểm soát (P < 0.05). Tỷ lệ Treg/Th17 trong nhóm PCOS thấp hơn đáng kể (P < 0.001). Nồng độ Interleukin (IL)-6, IL-17, và IL-23 cao hơn đáng kể, trong khi mức IL-10 và yếu tố tăng trưởng chuyển đổi-β (TGF-β) thấp hơn đáng kể trong nhóm PCOS (P < 0.001). Phân tích tương quan hạng Spearman cho thấy có mối tương quan âm mạnh giữa mức HSP70 huyết thanh với tỷ lệ Treg/Th17, mức IL-10 và TGF-β. Ngược lại, mức HSP70 có tương quan dương đáng kể với mức IL-6, IL-17, IL-23, LH, insulin và glucose. Mức độ HSP70 bất thường có liên quan đến sự mất cân bằng Treg/Th17 và các cytokine tương ứng, cho thấy rằng HSP70 có thể đóng vai trò quan trọng trong bệnh sinh miễn dịch của PCOS.

Từ khóa

#Hội chứng buồng trứng đa nang #HSP70 #tế bào T điều hòa #tế bào T hỗ trợ 17 #cytokine.

Tài liệu tham khảo

Escobar-Morreale HF. Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment. Nat Rev Endocrinol. 2018;14(5):270–84. Neven ACH, Laven J, Teede HJ, et al. A summary on polycystic ovary syndrome: diagnostic criteria, prevalence, clinical manifestations, and management according to the latest international guidelines. Semin Reprod Med. 2018;36(1):5–12. Yau TT, Ng NY, Cheung LP, et al. Polycystic ovary syndrome: a common reproductive syndrome with long-term metabolic consequences. Hong Kong Med J. 2017;23(6):622–34. De Leo V, Musacchio MC, Cappelli V, et al. Genetic, hormonal and metabolic aspects of PCOS: an update. Reprod Biol Endocrinol. 2016;14(1):38. Tsan MF, Gao B. Heat shock protein and innate immunity. Cell Mol Immunol. 2004;1(4):274–9. Dokladny K, Myers OB, Moseley PL. Heat shock response and autophagy–cooperation and control. Autophagy. 2015;11(2):200–13. Mayer MP. Hsp70 chaperone dynamics and molecular mechanism. Trends Biochem Sci. 2013;38(10):507–14. Jansen E, Laven JS, Dommerholt HB, et al. Abnormal gene expression profiles in human ovaries from polycystic ovary syndrome patients. Mol Endocrinol. 2004;18(12):3050–63. Saghafi N, Pourali L, Ghavami Ghanbarabadi V, et al. Serum heat shock protein 70 in preeclampsia and normal pregnancy: a systematic review and meta-analysis. Int J Reprod Biomed. 2018;16(1):1–8. Mahmoud FF, Haines D, Dashti AA, et al. Correlation between heat shock proteins, adiponectin, and T lymphocyte cytokine expression in type 2 diabetics. Cell Stress Chaperones. 2018;23(5):955–65. Elmallah MIY, Cordonnier M, Vautrot V, et al. Membrane-anchored heat-shock protein 70 (Hsp70) in cancer. Cancer Lett. 2020;469:134–41. Qu B, Zhao Q, Ma Q, et al. Overexpression of miR-144–3p alleviates polycystic ovaries syndrome through targeting expression of HSP-70. Gene therapy. 2020;Online ahead of print. Littman DR, Rudensky AY. Th17 and regulatory T cells in mediating and restraining inflammation. Cell. 2010;140(6):845–58. Fasching P, Stradner M, Graninger W, et al. Therapeutic potential of targeting the Th17/Treg axis in autoimmune disorders. Molecules. 2017;22(1):134. Rostamtabar M, Esmaeilzadeh S, Tourani M, et al. Pathophysiological roles of chronic low-grade inflammation mediators in polycystic ovary syndrome. J Cell Physiol. 2021;236(2):824–38. Wu R, Fujii S, Ryan NK, et al. Ovarian leukocyte distribution and cytokine/chemokine mRNA expression in follicular fluid cells in women with polycystic ovary syndrome. Hum Reprod. 2007;22(2):527–35. Nasri F, Doroudchi M, Namavar Jahromi B, et al. T helper cells profile and CD4+CD25+Foxp3+Regulatory T cells in polycystic ovary syndrome. Iran J Immunol. 2018;15(3):175–85. Pileggi GS, Clemencio AD, Malardo T, et al. New strategy for testing efficacy of immunotherapeutic compounds for diabetes in vitro. BMC Biotechnol. 2016;16(1):40. Weng L, Cao X, Han L, et al. Association of increased Treg and Th17 with pathogenesis of moyamoya disease. Scientific Rep. 2017;7(1):3071. Luo J, Zhang M, Yan B, et al. Imbalance of Th17 and Treg in peripheral blood mononuclear cells of active tuberculosis patients. Braz J Infect Dis. 2017;21(2):155–61. Rotterdam EA-SPcwg. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19(1):41–7. Lee GR. The balance of Th17 versus Treg cells in autoimmunity. Int J Mol Sci. 2018;19(3):730. Modzelewski J, Kajdy A, Rabijewski M. The role of lymphocytes in fetal development and recurrent pregnancy loss. Ginekol Pol. 2019;90(2):109–13. Eghbal-Fard S, Yousefi M, Heydarlou H, et al. The imbalance of Th17/Treg axis involved in the pathogenesis of preeclampsia. J Cell Physiol. 2019;234(4):5106–16. Gallinelli A. Correlations between concentrations of interleukin-12 and interleukin-13 and lymphocyte subsets in the follicular fluid of women with and without polycystic ovary syndrome. Fertil Steril. 2003;79(6):1365–72. Krishna MB, Joseph A, Subramaniam AG, et al. Reduced Tregs in peripheral blood of PCOS patients - a consequence of aberrant Il2 signaling. J Clin Endocrinol Metab. 2015;100(1):282–92. Leposavic G, Perisic M, Kosec D, et al. Neonatal testosterone imprinting affects thymus development and leads to phenotypic rejuvenation and masculinization of the peripheral blood T-cell compartment in adult female rats. Brain Behav Immun. 2009;23(2):294–304. Page ST, Plymate SR, Bremner WJ, et al. Effect of medical castration on CD4+ CD25+ T cells, CD8+ T cell IFN-gamma expression, and NK cells: a physiological role for testosterone and/or its metabolites. Am J Physiol Endocrinol Metab. 2006;290(5):E856-863. Wu G, Hu X, Ding J, et al. Abnormal expression of HSP70 may contribute to PCOS pathology. J Ovarian Res. 2019;12(1):74. Wang J, Wu D, Guo H, et al. Hyperandrogenemia and insulin resistance: The chief culprit of polycystic ovary syndrome. Life Sci. 2019;236:116940. Matulewicz N, Karczewska-Kupczewska M. Insulin resistance and chronic inflammation. Postepy Hig Med Dosw (Online). 2016;70:1245–58. Tao L, Liu H, Gong Y. Role and mechanism of the Th17/Treg cell balance in the development and progression of insulin resistance. Mol Cell Biochem. 2019;459(1–2):183–8. Witkin SS, Kanninen TT, Sisti G. The role of Hsp70 in the regulation of autophagy in gametogenesis, pregnancy, and parturition. Adv Anat Embryol Cell Biol. 2017;222:117–27. Gao H, Meng J, Xu M, et al. Serum heat shock protein 70 concentration in relation to polycystic ovary syndrome in a non-obese chinese population. PLoS ONE. 2013;8(6):e67727. Narayansingh RM, Senchyna M, Vijayan MM, et al. Expression of prostaglandin G/H synthase (PGHS) and heat shock protein-70 (HSP-70) in the corpus luteum (CL) of prostaglandin F2 alpha-treated immature superovulated rats. Can J Physiol Pharmacol. 2004;82(6):363–71. Rodriguez-Iturbe B, Lanaspa MA, Johnson RJ. The role of autoimmune reactivity induced by heat shock protein 70 in the pathogenesis of essential hypertension. Br J Pharmacol. 2019;176(12):1829–38. Tsan MF, Gao B. Heat shock proteins and immune system. J Leukoc Biol. 2009;85(6):905–10. Wieten L, Broere F, van der Zee R, et al. Cell stress induced HSP are targets of regulatory T cells: a role for HSP inducing compounds as anti-inflammatory immuno-modulators? FEBS Lett. 2007;581(19):3716–22. Chen Z, Barbi J, Bu S, et al. The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3. Immunity. 2013;39(2):272–85. Radons J. The human HSP70 family of chaperones: where do we stand? Cell Stress Chaperones. 2016;21(3):379–404. Cwiklinska H, Cichalewska-Studzinska M, Selmaj KW, et al. The heat shock protein HSP70 promotes Th17 genes' expression via specific regulation of microRNA. Int J Mol Sci. 2020;21(8):2823. Zanin-Zhorov A, Cohen IR. Signaling via TLR2 and TLR4 directly down-regulates T cell effector functions: the regulatory face of danger signals. Front Immunol. 2013;4:211. Hu M, Zhang Y, Li X, et al. TLR4-associated IRF-7 and NFkappaB signaling act as a molecular link between androgen and metformin activities and cytokine synthesis in the PCOS endometrium. J Clin Endocrinol Metab. 2021;106(4):1022–40. Kawai T, Akira S. TLR signaling. Semin Immunol. 2007;19(1):24–32. Tsan MF, Gao B. Cytokine function of heat shock proteins. Am J Physiol Cell Physiol. 2004;286(4):C739-744. Guo D, Chen Y, Wang S, et al. Exosomes from heat-stressed tumour cells inhibit tumour growth by converting regulatory T cells to Th17 cells via IL-6. Immunology. 2018;154(1):132–43. Kohno H, Takahashi N, Shinohara T, et al. Receptor-mediated suppression of cardiac heat-shock protein 72 expression by testosterone in male rat heart. Endocrinology. 2007;148(7):3148–55. Barber TM, Franks S. Obesity and polycystic ovary syndrome. Clin Endocrinol (Oxf). 2021;95:531–41. Morteza A, Nakhjavani M, Larry M, et al. Heat shock protein 70 and albuminuria in patients with type 2 diabetes: a matched case control study. Cell Stress Chaperones. 2013;18(6):815–9. Nakhjavani M, Morteza A, Asgarani F, et al. The dual behavior of heat shock protein 70 and asymmetric dimethylarginine in relation to serum CRP levels in type 2 diabetes. Gene. 2012;498(1):107–11. Garamvolgyi Z, Prohaszka Z, Rigo J Jr, et al. Increased circulating heat shock protein 70 (HSPA1A) levels in gestational diabetes mellitus: a pilot study. Cell Stress Chaperones. 2015;20(4):575–81. Arredouani A, Diane A, Khattab N, et al. DNAJB3 attenuates metabolic stress and promotes glucose uptake by eliciting Glut4 translocation. Sci Rep. 2019;9(1):4772. Simar D, Jacques A, Caillaud C. Heat shock proteins induction reduces stress kinases activation, potentially improving insulin signalling in monocytes from obese subjects. Cell Stress Chaperones. 2012;17(5):615–21. Krause M, Keane K, Rodrigues-Krause J, et al. Elevated levels of extracellular heat-shock protein 72 (eHSP72) are positively correlated with insulin resistance in vivo and cause pancreatic beta-cell dysfunction and death in vitro. Clin Sci (Lond). 2014;126(10):739–52. Fonseca HP, Brondi RS, Piovesan FX, et al. Anti-Mullerian hormone and insulin resistance in polycystic ovary syndrome. Gynecol Endocrinol. 2014;30(9):667–70. Wiweko B, Indra I, Susanto C, et al. The correlation between serum AMH and HOMA-IR among PCOS phenotypes. BMC Res Notes. 2018;11(1):114. Chun S. 1-h Postprandial glucose level is related to the serum anti-Mullerian hormone level in women with polycystic ovary syndrome. Gynecol Endocrinol. 2015;31(10):815–8. Cassar S, Teede HJ, Moran LJ, et al. Polycystic ovary syndrome and anti-Mullerian hormone: role of insulin resistance, androgens, obesity and gonadotrophins. Clin Endocrinol (Oxf). 2014;81(6):899–906. Chen MJ, Yang WS, Chen CL, et al. The relationship between anti-Mullerian hormone, androgen and insulin resistance on the number of antral follicles in women with polycystic ovary syndrome. Hum Reprod. 2008;23(4):952–7.