МикроРНК как регуляторы экспрессии интерлейкина-6 у пациентов с ревматоидным артритом

Интерлейкин-6 (ИЛ-6) это цитокин-прототип, обладающий плейотропной и избыточной функциональной активностью, который отвечает за созревание воспалительного инфильтрата, способствуя миграции нейтрофилов и инфильтрации мононуклеарных клеток, действует как хеморецептор для моноцитов в очаге воспаления. Эти механизмы играют важную роль в развитии и терапии ревматоидного артрита (РА). Малые некодирующие рибонуклеиновые кислоты (микроРНК) могут регулировать уровни ИЛ-6 в периферической крови и очаге воспаления путем регуляции экспрессии гена IL6 , кодирующего этот цитокин. Понимание роли микроРНК при РА может помочь в поиске ключа к разработке инновационных методов диагностики и персонализированных подходов к лечению этого ревматологического заболевания. Цель настоящего обзора состоит в обновлении знаний об эпигенетических биомаркерах РА и систематизации результатов клинических исследований взаимосвязи между экспрессией циркулирующих микроРНК и уровнем циркулирующего ИЛ-6 у пациентов с РА. Авторами проведен поиск публикаций в наукоемких базах данных PubMed, ClinicalKey, Scopus, Cochrane Database, Google Scholar, eLibrary.ru с использованием ключевых слов и их комбинаций. Были проанализированы публикации за 2014–2025 гг., включая оригинальные клинические исследования РА. В результате этого описательного обзора показано, что циркулирующие микроРНК могут рассматриваться как перспективные молекулярные биомаркеры РА. Однако пока внедрение результатов эпигенетических исследований в реальную клиническую практику ревматолога затруднено из-за неоднозначных результатов ранее проведенных исследований и необходимости учета как прямой, так и обратной взаимосвязи изменений уровней изученных циркулирующих микроРНК, а также уровней циркулирующего ИЛ-6 в крови у пациентов с РА.

1. Nazipova NN. Diversity of non-coding RNAs in eukaryotic genomes. Mathematical Biology and Bioinformatics . 2021;16(2):256–298. DOI: https://doi.org/10.17537/2021.16.256.

2. Evangelatos G, Fragoulis GE, Koulouri V, Lambrou GI, Tektonidou MG, Iliopoulos A. MicroRNAs in rheumatoid arthritis: From pathogenesis to clinical impact. Autoimmunity Reviews . 2019;18:102391. DOI: https://doi.org/10.1016/j.autrev.2019.102391.

3. Yang S, Yang M, Xie H, Wang Z, Wang H, Wang J. Role of miRNAs in Rheumatoid Arthritis Therapy. Cells . 2023;12(13):1749. DOI: https://doi.org/10.3390/cells12131749.

4. Nakasa T, Nagata Y, Yamasaki K, Ochi M. A mini-review: MicroRNA in arthritis. Physiological Genomics . 2011;43(10):566–570. DOI: https://doi.org/10.1152/physiolgenomics.00142.2010.

5. Li B, Xiao Y, Xing D, Guo Q, Jia J. Circulating interleukin-6 and rheumatoid arthritis: A Mendelian randomization meta-analysis. Medicine . 2016;95(23):e3855. DOI: https://doi.org/10.1097/MD.0000000000003855.

6. Ilyin AA, Deberdeeva KI, Volkov KA, Simakova VO, Bulatova AYu, Bogdanova TM. Interleukin-6: Pathophysiology, diagnostic significance. Modern problems of science and education . 2025;(4). (In Russ.). DOI: https://doi.org/10.17513/spno.34160.

7. Tanaka T, Narazaki M, Kishimoto T. Immunotherapeutic implications of IL-6 blockade for cytokine storm. Immunotherapy. 2016;8(9):959–970. DOI: https://doi.org/10.2217/imt-2016-0020.

8. Lennert A, Fardo DW. Detecting novel micro RNAs in rheumatoid arthritis with gene-based association testing. Clinical and Experimental Rheumatology . 2017;35(4):586–592. PMID: https://pubmed.ncbi.nlm.nih.gov/28134081/.

9. Kang S, Tanaka T, Narazaki M, Kishimoto T. Targeting Interleukin-6 signaling in clinic. Immunity . 2019;50(4):1007–1023. DOI: https://doi.org/10.1016/j.immuni.2019.03.026.

10. Yoshida Y, Tanaka T. Interleukin 6 and rheumatoid arthritis. BioMed Research International . 2014;2014:698313. DOI: https://doi.org/10.1155/2014/698313.

11. Pandolfi F, Franza L, Carusi V, Altamura S, Andriollo G, Nucera E. Interleukin-6 in rheumatoid arthritis. International Journal of Molecular Sciences . 2020;21 (15):5238. DOI: https://doi.org/10.3390/ijms21155238.

12. Mandal S, Abebe F, Chaudhary J. –174G/C polymorphism in the interleukin-6 promoter is differently associated with prostate cancer incidence depending on race. Genetics and Molecular Research . 2014;13(1):139151. DOI: https://doi.org/10.4238/2014.January.10.5.

13. Lau CS. Burden of rheumatoid arthritis and forecasted prevalence to 2050. The Lancet Rheumatology . 2023;5(10):e567–e568. DOI: https://doi.org/10.1016/S2665-9913(23)00240-0.

14. Paudel ML, Li R, Naik C, Shadick N, Weinblatt ME, Solomon DH. Prevalence and characteristics of adults with difficult-to-treat rheumatoid arthritis in a large patient registry. Rheumatology (Oxford) . 2025;64(3):11021110. DOI: https://doi.org/10.1093/rheumatology/keae318.

15. De Hair MJH, Jacobs JWG, Schoneveld JLM, van Laar JM. Difficult-to-treat rheumatoid arthritis: an area of unmet clinical need. Rheumatology (Oxford) . 2018;57(7):1135–1144. DOI: https://doi.org/10.1093/rheumatology/kex349.

16. Paradowska-Gorycka A, Stypińska B. MicroRNAs in rheumatoid arthritis: From pathogenesis to clinical utility. Rheumatoid Arthritis Other Perspectives towards a Better Practice . 2017. DOI: https://doi.org/10.5772/67320.

17. Maunder D, Brown PM, Barron-Millar B, Lendrem DW, Naamane N, Macdonald J, et al. Micro-RNA content of circulating extracellular vesicles in early rheumatoid arthritis as biomarkers and mediators of methotrexate efficacy. Rheumatology (Oxford) . 2024;63(8):2259–2267. DOI: https://doi.org/10.1093/rheumatology/kead569.

18. Yang S, Yang Y. Downregulation of microRNA-221 decreases migration and invasion in fibroblast-like synoviocytes in rheumatoid arthritis. Molecular Medicine Reports . 2015;12(2):2395–2401. DOI: https://doi.org/10.3892/mmr.2015.3621.

19. Hassine HB, Boumiza A, Sghiri R, Baccouche K, Boussaid I, Atig A, et al. Micro RNA-146a but not IRAK1 is associated with rheumatoid arthritis in the Tunisian population. Genetic Testing and Molecular Biomarkers . 2017;21(2):92–96. DOI: https://doi.org/10.1089/gtmb.2016.0270.

20. Ali YBM, Hasan NMA, El-maadawy EA, Bassyouni IH, El-Shahat M, Talaat RM. Association between IL-6, miRNA-146a, MALAT1 genetic polymorphisms and risk of rheumatoid arthritis. Personalized Medicine. 2024;21(5):277–294. DOI: https://doi.org/10.1080/17410541.2024.2393072.

21. Lu MC, Yu CL, Chen HC, Yu HC, Huang HB, Lai NS. Increased miR-223 expression in T cells from patients with rheumatoid arthritis leads to decreased insulin-like growth factor-1-mediated interleukin-10 production. Clinical and Experimental Immunology . 2014;177(3):641–651. DOI: https://doi.org/10.1111/cei.12374.

22. Ogando J, Tardáguila M, Díaz-Alderete A, Usategui A, Miranda-Ramos V, Martínez-Herrera DJ, et al. Notch-regulated miR-223 targets the aryl hydrocarbon receptor pathway and increases cytokine production in macrophages from rheumatoid arthritis patients. Scientific Reports . 2016;6:20223. DOI: https://doi.org/10.1038/srep20223.

23. Taha M, Shaker OG, Abdelsalam E, Taha N. Serum a proliferation-inducing ligand and MicroRNA-223 are associated with rheumatoid arthritis: Diagnostic and prognostic implications. Molecular Medicine . 2020;26(1):92. DOI: https://doi.org/10.1186/s10020-020-00199-7.

24. Moran-Moguel MC, Petarra-del Rio S, Mayorquin-Galvan EE, Zavala-Cerna MG. Rheumatoid arthritis and miRNAs: A critical review through a functional view. Journal of Immunology Research . 2018;2018:2474529. DOI: https://doi.org/10.1155/2018/2474529.

25. Wang L, Zhao Q, Wang N, Ding Y, Kong L, Wang J. Circ_0000396 inhibits rheumatoid arthritis synovial fibroblast growth and inflammatory response via miR-203/HBP1 axis. Journal of Biological Research Thessaloniki . 2021;28(1):1. DOI: https://doi.org/10.1186/s40709-20-00131-4.

26. Lai NS, Yu HC, Chen HC, Yu CL, Huang HB, Lu MC. Decreased expression of microRNA let-7a in T cells from patients with rheumatoid arthritis. Immunobiology . 2015;220(11):1261–1266. DOI: https://doi.org/10.1016/j.imbio.2015.07.007.

27. Ebrahimiyan H, Ahmadzadeh A. miRNAs and rheumatoid arthritis: New update in expression pattern and pathogenicity. Rheumatology Research . 2021;6(3):123–137. DOI: https://doi.org/10.32592/RR.2021.6.3.123.

28. Kmiołek T, Paradowska-Gorycka A. miRNAs as Biomarkers and Possible Therapeutic Strategies in Rheumatoid Arthritis. Cells . 2022;11(3):452. DOI: https://doi.org/10.3390/cells11030452.

29. Mu N, Gu J, Huang T, Zhang C, Shu Z, Li M, et al. A novel NF-κB/YY1/microRNA-10a regulatory circuit in fibroblast-like synoviocytes regulates inflammation in rheumatoid arthritis. Scientific Reports . 2016;6:20059. DOI: https://doi.org/10.1038/srep20059.

30. Wu W, He C, Liu C, Cao AT, Xue X, Evans-Marin HL, et al. miR-10a inhibits dendritic cell activation and Th1/Th17 cell immune responses in IBD. Gut . 2015;64(11):1755–1764. DOI: https://doi.org/10.1136/gutjnl-2014-307980.

31. Chen Y, Xian PF, Yang L, Wang SX. MicroRNA-21 promotes proliferation of fibroblast-like synoviocytes through mediation of NF-κB nuclear translocation in a rat model of collagen-induced rheumatoid arthritis. BioMed Research International . 2016;2016:9279078. DOI: https://doi.org/10.1155/2016/9279078.

32. Zhang C, Fang L, Liu X, Nie T, Li R, Cui L, et al. miR-22 inhibits synovial fibroblasts proliferation and proinflammatory cytokine production in RASF via targeting SIRT1. Gene . 2020;724:144144. DOI: https://doi.org/10.1016/j.gene.2019.144144.

33. Huang Z, Xing S, Liu M, Deng W, Wang Y, Huang Z, et al. MiR-26a-5p enhances cells proliferation, invasion, and apoptosis resistance of fibroblast-like synoviocytes in rheumatoid arthritis by regulating PTEN/PI3K/ AKT pathway. Bioscience Reports . 2019;39(6):BSR20182192. DOI: https://doi.org/10.1042/BSR20182192.

34. Shi DL, Shi GR, Xie J, Du XZ, Yang H. MicroRNA-27a inhibits cell migration and invasion of fibroblast-like synoviocytes by targeting follistatin-like protein 1 in rheumatoid arthritis. Molecules and Cells . 2016;39(8):611–618. DOI: https://doi.org/10.14348/molcells.2016.0103.

35. Niederer F, Ospelt C, Brentano F, Hottiger MO, Gay RE, Gay S, et al. SIRT1 overexpression in the rheumatoid arthritis synovium contributes to survival of fibroblast-like synoviocytes and is negatively regulated by microRNA-29a. Arthritis and Rheumatology . 2011;63(7):1855–1864. DOI: https://doi.org/10.1002/art.30351.

36. Alsaleh G, François A, Philippe L, Gong YZ, Bahram S, Cetin S, et al. MiR-30a-3p negatively regulates BAFF synthesis in systemic sclerosis and rheumatoid arthritis fibroblasts. PLoS One . 2014;9(10):e111266. DOI: https://doi.org/10.1371/journal.pone.0111266.

37. Wu H, Zhou X, Wang X, Cheng W, Hu X, Wang Y, et al. miR-34a in extracellular vesicles from bone marrow mesenchymal stem cells reduces rheumatoid arthritis inflammation via the cyclin I/ATM/ATR/p53 axis. Journal of Cellular and Molecular Medicine . 2021;25(4):1754–1765. DOI: https://doi.org/10.1111/jcmm.15857.

38. Wei Q, Lv F, Zhang H, Wang X, Geng Q, Zhang X, et al. MicroRNA-101–3p inhibits fibroblast-like synoviocyte proliferation and inflammation in rheumatoid arthritis by targeting PTGS2. Bioscience Reports . 2020;40(1):BSR20191136. DOI: https://doi.org/10.1042/BSR20191136.

39. Larsson C, Andersson KME, Nadali M, Silfverswärd ST, Bokarewa MI, Erlandsson MC. MicroRNA and interleukin 6 interplay in the adipose tissue of rheumatoid arthritis patients. Clinical and Experimental Rheumatology . 2023;41(1):32–40. DOI: https://doi.org/10.55563/clinexprheumatol/f4vlvt.

40. Yang B, Ge Y, Zhou Y, Wang J, Xie X, Li S, et al. miR-124a inhibits the proliferation and inflammation in rheumatoid arthritis fibroblast-like synoviocytes via targeting PIK3/NF-κB pathway. Cell Biochemistry and Function . 2019;37(4):208–215. DOI: https://doi.org/10.1002/cbf.3386.

41. Peng T, Ji D, Jiang Y. Long non-coding RNA GAS5 suppresses rheumatoid arthritis progression via miR128-3p/HDAC4 axis. Molecular and Cellular Biochemistry . 2021;476(6):2491–2501. DOI: https://doi.org/10.1007/s11010-021-04098-1.

42. Du J, Zhang F, Guo J. miR-137 decreases proliferation, migration and invasion in rheumatoid arthritis fibroblast-like synoviocytes. Molecular Medicine Reports . 2018;17(2):3312–3317. DOI: https://doi.org/10.3892/mmr.2018.8471.

43. Hong BK, You S, Yoo SA, Park D, Hwang D, Cho CS, et al. MicroRNA-143 and –145 modulate the phenotype of synovial fibroblasts in rheumatoid arthritis. Experimental & Molecular Medicine . 2017;49(8):e363. DOI: https://doi.org/10.1038/emm.2017.108.

44. Guo J, Du J, Fei D, Xing J, Liu J, Lu H. miR-152 inhibits rheumatoid arthritis synovial fibroblast proliferation and induces apoptosis by targeting ADAM10. International Journal of Molecular Medicine . 2018;41(2):643650. DOI: https://doi.org/10.3892/ijmm.2018.3636.

45. Chakraborty C, Sharma AR, Sharma G, Priya Doss CG, Lee SS. Therapeutic miRNA and siRNA: Moving from bench to clinic as next generation medicine. Molecular Therapy Nucleic Acids . 2017;8:132–143. DOI: https://doi.org/10.1016/j.omtn.2017.06.005.

46. Andonian BJ, Chou CH, Ilkayeva OR, Koves TR, Connelly MA, Kraus WE, et al. Plasma microRNAs in established rheumatoid arthritis relate to adiposity and altered plasma and skeletal muscle cytokine and metabolic profiles. Frontiers in Immunology . 2019;10:1475. DOI: https://doi.org/10.3389/fimmu.2019.01475.

47. Najm A, Masson FM, Preuss P, Georges S, Ory B, Quillard T, et al. MicroRNA-17–5p reduces inflammation and bone erosions in mice with collagen-induced arthritis and directly targets the JAK/STAT pathway in rheumatoid arthritis fibroblast-like synoviocytes. Arthritis and Rheumatology . 2020;72(12):2030–2039. DOI: https://doi.org/10.1002/art.41434.

48. Horak M, Zlamal F, Iliev R, Kucera J, Cacek J, Svobodova L, et al. Exercise-induced circulating microRNA changes in athletes in various training scenarios. PLoS One . 2018;13(1):e0191060. DOI: https://doi.org/10.1371/journal.pone.0191060.

49. Abdeen HM, Gharbia OM, Bassiouni SARA, Zaki MES, Abdullah H, Morsi HK. Micro RNA-23b as a potential biomarker in rheumatoid arthritis disease activity and severity: Clinical, laboratory, and radiological cross-sectional study. Egyptian Rheumatology and Rehabilitation . 2021;48(1):39. DOI: https://doi.org/10.1186/s43166-021-00090-1.

50. Tan AL. Thank you to the reviewers of rheumatology advances in practice 2022. Rheumatology Advances in Practice . 2023;7(1):rkad013. DOI: https://doi.org/10.1093/rap/rkad013.

51. Yang JJ, Ng JPL, Zhang K, Liu L, Wong VKW. Pathogenic Role of microRNA in Rheumatoid Arthritis. Rheumatoid Arthritis Other Perspectives towards a Better Practice . 2021. DOI: https://doi.org/10.5772/intechopen.99212.

52. Balchin C, Tan AL, Wilson OJ, McKenna J, Stavropoulos-Kalinoglou A. The role of microRNAs in regulating inflammation and exercise-induced adaptations in rheumatoid arthritis. Rheumatology Advances in Practice . 2023;7(1):rkac110. DOI: https://doi.org/10.1093/rap/rkac110.

53. Ang FJ, Zhou HY, Zhou LF, Wen YH, Gai HH, Wu GM. MicroRNA-421 promotes inflammatory response of fibroblast-like synoviocytes in rheumatoid arthritis by targeting SPRY1. European Review for Medical and Pharmacological Sciences . 2019;23(19):8186–8193. DOI: https://doi.org/10.26355/eurrev_201910_19131.

54. Jiang C, Wu X, Li X, Li M, Zhang W, Tao P, et al. Loss of microRNA-147 function alleviates synovial inflammation through ZNF148 in rheumatoid and experimental arthritis. European Journal of Immunology . 2021;51(8):2062–2073. DOI: https://doi.org/10.1002/eji.202048991.

55. Liang X, Xu Z, Yuan M, Zhang Y, Zhao B, Wang J, et al. MicroRNA-16 suppresses the activation of inflammatory macrophages in atherosclerosis by targeting PDCD4. International Journal of Molecular Medicine . 2016;37(4):967–975. DOI: https://doi.org/10.3892/ijmm.2016.2496.

56. Araki K, Mokuda S, Kohno H, Oka N, Watanabe H, Ishitoku M, et al. Hsa-miR-21–5p is induced by interleukin-6 and affects multiple pathogenic factors associated with fibroblast-like synoviocytes in rheumatoid arthritis. Scientific Reports . 2025;15:19416. DOI: https://doi.org/10.1038/s41598-025-02840-z.

57. De la Rosa IA, Perez-Sanchez C, Ruiz-Limon P, Patino-Trives A, Torres-Granados C, Jimenez-Gomez Y, et al. Impaired microRNA processing in neutrophils from rheumatoid arthritis patients confers their pathogenic profile. Modulation by biological therapies. Haematologica . 2020;105(9):2250–2261. DOI: https://doi.org/10.3324/haematol.2019.231944.

58. Quero L, Tiaden AN, Hanser E, Roux J, Laski A, Hall J, et al. miR-221–3p Drives the Shift of M2-Macrophages to a Pro-Inflammatory Function by Suppressing JAK3/STAT3 Activation. Frontiers in Immunology . 2020;10:3087. DOI: https://doi.org/10.3389/fimmu.2019.03087.

59. Zhang MF, Yang P, Shen MY, Wang X, Gao NX, Zhou XP, et al. MicroRNA-26b-5p alleviates murine collagen-induced arthritis by modulating Th17 cell plasticity. Cellular Immunology . 2021;365:104382. DOI: https://doi.org/10.1016/j.cellimm.2021.104382.

60. Ibrahim SSA, Kandil LS, Ragab GM, El-Sayyad SM. Micro RNAs 26b, 20a inversely correlate with GSK-3β/ NF-κB/NLRP-3 pathway to highlight the additive promising effects of atorvastatin and quercetin in experimental induced arthritis. International Immunopharmacology . 2021;99:108042. DOI: https://doi.org/10.1016/j.intimp.2021.108042.

61. Zhou L, Wang J, Li J, Li T, Chen Y, June RR, et al. 1,25-Dihydroxyvitamin D3 ameliorates collagen-induced Frontiers arthritis via suppression of Th17 cells through miR-124 mediated inhibition of IL-6 signaling. in Immunology . 2019;10:178. DOI: https://doi.org/10.3389/fimmu.2019.00178.

62. Zhao C, Li X, Yang Y, Li Z, Li M, Tan Q, et al. An analysis of Treg/Th17 cells imbalance associated microRNA networks regulated by moxibustion therapy on Zusanli (ST36) and Shenshu (BL23) in mice with collagen induced arthritis. American Journal of Translational Research . 2019;11(7):4029–4045. PMID: https://pubmed.ncbi.nlm.nih.gov/31396316/.

63. Cai Y, Jiang C, Wang B, Yuan Q, Gu Y, et al. miR-449a inhibits cell proliferation, migration, and inflammation by regulating high-mobility group box protein 1 and forms a mutual inhibition loop with Yin Yang 1 in rheumatoid arthritis fibroblast-like synoviocytes. Arthritis Research & Therapy . 2019;21(1):134. DOI: https://doi.org/10.1186/s13075-019-1920-0.

64. Zhu H, Fu J, Chen S, Li X, Liang H, Hou Y, et al. FC-99 reduces macrophage tenascin-C expression by upregulating miRNA-494 in arthritis. International Immunopharmacology . 2020;79:106105. DOI: https://doi.org/10.1016/j.intimp.2019.106105.

65. Wang Y, Zheng F, Gao G, Yan S, Zhang L, Wang L, et al. MiR-548a-3p regulates inflammatory response via TLR4/NF-κB signaling pathway in rheumatoid arthritis. Journal of Cellular Biochemistry . 2019;120(2):11331140. DOI: https://doi.org/10.1002/jcb.26659.

66. Pan F, Xiang H, Yan J, Hong L, Zhang L, Liu Y, et al. Dendritic cells from rheumatoid arthritis patient peripheral blood induce Th17 cell differentiation via miR-363/Integrin αv/TGF-β Axis. Scandinavian Journal of Immunology . 2017;85(6):441–449. DOI: https://doi.org/10.1111/sji.12550.

67. Li F, Xu J, Zheng J, Sokolove J, Zhu K, Zhang Y, et al. Association between interleukin-6 gene polymorphisms and rheumatoid arthritis in Chinese Han population: A case-control study and a meta-analysis. Scientific Reports . 2014;4:5714. DOI: https://doi.org/10.1038/srep05714.

68. Nagy G, Roodenrijs NMT, Welsing PMJ, Kedves M, Hamar A, van der Goes MC, et al. EULAR definition of difficult-to-treat rheumatoid arthritis. Annals of the Rheumatic Diseases . 2021;80(1):31–35. DOI: https:// doi.org/10.1136/annrheumdis-2020-217344.

69. Novella-Navarro M, Ruiz-Esquide V, Torres-Ortiz G, Chacur CA, Tornero C, Fernández-Fernández E, et al. A paradigm of difficult-to-treat rheumatoid arthritis: Subtypes and early identification. Clinical and Experimental Rheumatology . 2023;41(5):1114–1119. DOI: https://doi.org/10.55563/clinexprheumatol/7mscci.