Current status and progress of interleukin<b>-</b>6 in Takayasu arteritis_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

WU Zhiyuan ¹ , MIAO Yuqing ¹ , DIAO Yongpeng ¹ ,  LI Yongjun ^1,2,3

1. Department of Vascular Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, P. R. China;
2. Chinese Academy of Medical Sciences, Peking Union Medical College Graduate School, Beijing 100730, P. R. China;
3. Peking University Health Science Center, Beijing 100191, P. R. China;

Corresponding author：

LI Yongjun, Email: liyongjun4679@bjhmoh.cn

Keywords：

Takayasu arteritis; interleukin-6; tocilizumab; cytokines

DOI：

10.7507/1007-9424.202211001

Video：

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Objective To summarize the research status and progress of interleukin-6 (IL-6) in Takayasu arteritis (TAK). Method Recent literature published at home and abroad about the study of IL-6 in the TAK was reviewed and analyzed. Results IL-6 was a pro-inflammatory cytokine secreted by a variety of cells, which participated in a variety of inflammatory and immune reactions, and played an important role in the progress of TAK. The expression levels of IL-6 in the peripheral blood and vascular wall tissues of patients with TAK were increased. The gene polymorphism of IL-6 might be related to the occurrence of TAK. Tocilizumab, an IL-6 receptor antagonist, was effective and safe in the treatment of TAK. Conclusions IL-6 can be used as one of the monitoring indicators for the active phase and recurrence of TAK. IL-6 receptor antagonist can be used as the treatment choice of TAK, but the application results in different stages of TAK are still worth expecting.

Citation： WU Zhiyuan, MIAO Yuqing, DIAO Yongpeng, LI Yongjun. Current status and progress of interleukin-6 in Takayasu arteritis. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2023, 30(4): 490-493. doi: 10.7507/1007-9424.202211001 Copy

1.	中华医学会风湿病学分会. 大动脉炎诊断及治疗指南. 中华风湿病学杂志, 2011, 15(2): 119-120.
2.	Diao Y, Yan S, Premaratne S, et al. Surgery and endovascular management in patients with Takayasu’s arteritis: a ten-year retrospective study. Ann Vasc Surg, 2020, 63: 34-44.
3.	陈作观, 刁永鹏, 刘静思, 等. 大动脉炎外科分型研究进展. 中华医学杂志, 2016, 96(28): 2277-2280.
4.	刁永鹏, 陈跃鑫, 闫盛, 等. 大动脉炎116例外科手术及腔内治疗效果及安全性分析. 中华医学杂志, 2016, 96(6): 447-450.
5.	Kishimoto T, Ishizaka K. Regulation of antibody response in vitro. Ⅶ. Enhancing soluble factors for IgG and IgE antibody response. J Immunol, 1973, 111(4): 1194-205.
6.	Hirano T, Yasukawa K, Harada H, et al. Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature, 1986, 324(6092): 73-76.
7.	Papadaki G, Goutakoli P, Tiniakou I, et al. IL-6 signaling attenuates TNF-α production by plasmacytoid dendritic cells in rheumatoid arthritis. J Immunol, 2022, 209(10): 1906-1917.
8.	Lv J, Han M, Xiang Z, et al. Chlorzoxazone alleviates experimental autoimmune encephalomyelitis via inhibiting IL-6 secretion of dendritic cells. J Immunol, 2022, 208(7): 1545-1553.
9.	Kamtchum-Tatuene J, Saba L, Heldner MR, et al. Interleukin-6 predicts carotid plaque severity, vulnerability, and progression. Circ Res, 2022, 131(2): e22-e33. doi: 10.1161/CIRCRESAHA.122.320877.
10.	Nishihara M, Aoki H, Ohno S, et al. The role of IL-6 in pathogenesis of abdominal aortic aneurysm in mice. PLoS One, 2017, 12(10): e0185923. doi: 10.1371/journal.pone.0185923.
11.	Jeremić V, Alempijević T, Mijatović S, et al. Clinical relevance of IL-6 gene polymorphism in severely injured patients. Bosn J Basic Med Sci, 2014, 14(2): 110-117.
12.	Jabłońska A, Zagrapan B, Neumayer C, et al. Polymorphisms in the IL-6 and TNF-α gene are associated with an increased risk of abdominal aortic aneurysm. Int J Cardiol, 2021, 329: 192-197.
13.	Danda D, Goel R, Danda S, et al. Interleukin-17F and interleukin-6 gene polymorphisms in Asian Indian patients with Takayasu arteritis. Hum Immunol, 2017, 78(7-8): 515-520.
14.	Gao Q, Lv N, Dang A, et al. Association of interleukin-6 and interleukin-10 expression, gene polymorphisms, and Takayasu arteritis in a Chinese Han population. Clin Rheumatol, 2019, 38(1): 143-148.
15.	Renauer PA, Saruhan-Direskeneli G, Coit P, et al. Identification of susceptibility loci in IL6, RPS9/LILRB3, and an intergenic locus on chromosome 21q22 in Takayasu arteritis in a genome-wide association study. Arthritis Rheumatol, 2015, 67(5): 1361-1368.
16.	Ortiz-Fernández L, Saruhan-Direskeneli G, Alibaz-Oner F, et al. Identification of susceptibility loci for Takayasu arteritis through a large multi-ancestral genome-wide association study. Am J Hum Genet, 2021, 108(1): 84-99.
17.	Kong X, Sawalha AH. Takayasu arteritis risk locus in IL6 represses the anti-inflammatory gene GPNMB through chromatin looping and recruiting MEF2-HDAC complex. Ann Rheum Dis, 2019, 78(10): 1388-1397.
18.	Terao C, Yoshifuji H, Matsumura T, et al. Genetic determinants and an epistasis of LILRA3 and HLA-B*52 in Takayasu arteritis. Proc Natl Acad Sci U S A, 2018, 115(51): 13045-13050.
19.	Goel R, Kabeerdoss J, Ram B, et al. Serum cytokine profile in Asian Indian patients with Takayasu arteritis and its association with disease activity. Open Rheumatol J, 2017, 11: 23-29.
20.	Pathadan AP, Tyagi S, Gupta MD, et al. The study of novel inflammatory markers in Takayasu arteritis and its correlation with disease activity. Indian Heart J, 2021, 73(5): 640-643.
21.	Sun Y, Kong X, Cui X, et al. The value of interleukin-6 in predicting disease relapse for Takayasu arteritis during 2-year follow-up. Clin Rheumatol, 2020, 39(11): 3417-3425.
22.	Noris M, Daina E, Gamba S, et al. Interleukin-6 and RANTES in Takayasu arteritis: a guide for therapeutic decisions? Circulation, 1999, 100(1): 55-60.
23.	Alibaz-Oner F, Yentür SP, Saruhan-Direskeneli G, et al. Serum cytokine profiles in Takayasu’s arteritis: search for biomarkers. Clin Exp Rheumatol. 2015, 33(2 Suppl 89): S-32-5.
24.	Tamura N, Maejima Y, Tezuka D, et al. Profiles of serum cytokine levels in Takayasu arteritis patients: potential utility as biomarkers for monitoring disease activity. J Cardiol, 2017, 70(3): 278-285.
25.	Gao Q, Wu ZY , Yu J, et al. Single-cell RNA sequencing revealed CD14⁺ monocytes increased in patients with Takayasu’s arteritis requiring surgical management. Front Cell Dev Biol, 2021, 9: 761300. doi: 10.3389/fcell.2021.761300.
26.	Li J, Wang Y, Wang Y, et al. Association between acute phase reactants, interleukin-6, tumor necrosis factor-α, and disease activity in Takayasu’s arteritis patients. Arthritis Res Ther, 2020, 22(1): 285. doi: 10.1186/s13075-020-02365-y.
27.	Maciejewski-Duval A, Comarmond C, Leroyer A, et al. mTOR pathway activation in large vessel vasculitis. J Autoimmun, 2018, 94: 99-109.
28.	Rathore U, Thakare DR, Patro P, et al. A systematic review of clinical and preclinical evidences for Janus kinase inhibitors in large vessel vasculitis. Clin Rheumatol, 2022, 41(1): 33-44.
29.	Kong X, Wu S, Dai X, et al. A comprehensive profile of chemokines in the peripheral blood and vascular tissue of patients with Takayasu arteritis. Arthritis Res Ther, 2022, 24(1): 49. doi: 10.1186/s13075-022-02740-x.
30.	Kong X, Sun Y, Ma L, et al. The critical role of IL-6 in the pathogenesis of Takayasu arteritis. Clin Exp Rheumatol. 2016, 34(3 Suppl 97): S21-S27.
31.	Kong X, Ma L, Ji Z, et al. Pro-fibrotic effect of IL-6 via aortic adventitial fibroblasts indicates IL-6 as a treatment target in Takayasu arteritis. Clin Exp Rheumatol. 2018, 36(1): 62-72.
32.	Chen R, Sun Y, Cui X, et al. Autophagy promotes aortic adventitial fibrosis via the IL-6/Jak1 signaling pathway in Takayasu’s arteritis. J Autoimmun, 2019, 99: 39-47.
33.	高擎, 吴志远, 李海洋, 等. 单细胞转录组测序在多发性大动脉炎肾动脉病变中的初步探索. 中国医学科学院学报, 2023, 45(1): 80-87.
34.	Nishimoto N, Nakahara H, Yoshio-Hoshino N, et al. Successful treatment of a patient with Takayasu arteritis using a humanized anti-interleukin-6 receptor antibody. Arthritis Rheum, 2008, 58(4): 1197-1200.
35.	Nakaoka Y, Isobe M, Takei S, et al. Efficacy and safety of tocilizumab in patients with refractory Takayasu arteritis: results from a randomised, double-blind, placebo-controlled, phase 3 trial in Japan (the TAKT study). Ann Rheum Dis, 2018, 77(3): 348-354.
36.	Harigai M, Miyamae T, Hashimoto H, et al. A multicentre, large-scale, observational study of tocilizumab in patients with Takayasu arteritis in Japan: The ACT-Bridge Study. Mod Rheumatol, 2022, roac099. doi: 10.1093/mr/roac099.
37.	Mekinian A, Saadoun D, Vicaut E, et al. Tocilizumab in treatment-naïve patients with Takayasu arteritis: TOCITAKA French prospective multicenter open-labeled trial. Arthritis Res Ther, 2020, 22(1): 218. doi: 10.1186/s13075-020-02311-y.

1. 中华医学会风湿病学分会. 大动脉炎诊断及治疗指南. 中华风湿病学杂志, 2011, 15(2): 119-120.
2. Diao Y, Yan S, Premaratne S, et al. Surgery and endovascular management in patients with Takayasu’s arteritis: a ten-year retrospective study. Ann Vasc Surg, 2020, 63: 34-44.
3. 陈作观, 刁永鹏, 刘静思, 等. 大动脉炎外科分型研究进展. 中华医学杂志, 2016, 96(28): 2277-2280.
4. 刁永鹏, 陈跃鑫, 闫盛, 等. 大动脉炎116例外科手术及腔内治疗效果及安全性分析. 中华医学杂志, 2016, 96(6): 447-450.
5. Kishimoto T, Ishizaka K. Regulation of antibody response in vitro. Ⅶ. Enhancing soluble factors for IgG and IgE antibody response. J Immunol, 1973, 111(4): 1194-205.
6. Hirano T, Yasukawa K, Harada H, et al. Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature, 1986, 324(6092): 73-76.
7. Papadaki G, Goutakoli P, Tiniakou I, et al. IL-6 signaling attenuates TNF-α production by plasmacytoid dendritic cells in rheumatoid arthritis. J Immunol, 2022, 209(10): 1906-1917.
8. Lv J, Han M, Xiang Z, et al. Chlorzoxazone alleviates experimental autoimmune encephalomyelitis via inhibiting IL-6 secretion of dendritic cells. J Immunol, 2022, 208(7): 1545-1553.
9. Kamtchum-Tatuene J, Saba L, Heldner MR, et al. Interleukin-6 predicts carotid plaque severity, vulnerability, and progression. Circ Res, 2022, 131(2): e22-e33. doi: 10.1161/CIRCRESAHA.122.320877.
10. Nishihara M, Aoki H, Ohno S, et al. The role of IL-6 in pathogenesis of abdominal aortic aneurysm in mice. PLoS One, 2017, 12(10): e0185923. doi: 10.1371/journal.pone.0185923.
11. Jeremić V, Alempijević T, Mijatović S, et al. Clinical relevance of IL-6 gene polymorphism in severely injured patients. Bosn J Basic Med Sci, 2014, 14(2): 110-117.
12. Jabłońska A, Zagrapan B, Neumayer C, et al. Polymorphisms in the IL-6 and TNF-α gene are associated with an increased risk of abdominal aortic aneurysm. Int J Cardiol, 2021, 329: 192-197.
13. Danda D, Goel R, Danda S, et al. Interleukin-17F and interleukin-6 gene polymorphisms in Asian Indian patients with Takayasu arteritis. Hum Immunol, 2017, 78(7-8): 515-520.
14. Gao Q, Lv N, Dang A, et al. Association of interleukin-6 and interleukin-10 expression, gene polymorphisms, and Takayasu arteritis in a Chinese Han population. Clin Rheumatol, 2019, 38(1): 143-148.
15. Renauer PA, Saruhan-Direskeneli G, Coit P, et al. Identification of susceptibility loci in IL6, RPS9/LILRB3, and an intergenic locus on chromosome 21q22 in Takayasu arteritis in a genome-wide association study. Arthritis Rheumatol, 2015, 67(5): 1361-1368.
16. Ortiz-Fernández L, Saruhan-Direskeneli G, Alibaz-Oner F, et al. Identification of susceptibility loci for Takayasu arteritis through a large multi-ancestral genome-wide association study. Am J Hum Genet, 2021, 108(1): 84-99.
17. Kong X, Sawalha AH. Takayasu arteritis risk locus in IL6 represses the anti-inflammatory gene GPNMB through chromatin looping and recruiting MEF2-HDAC complex. Ann Rheum Dis, 2019, 78(10): 1388-1397.
18. Terao C, Yoshifuji H, Matsumura T, et al. Genetic determinants and an epistasis of LILRA3 and HLA-B*52 in Takayasu arteritis. Proc Natl Acad Sci U S A, 2018, 115(51): 13045-13050.
19. Goel R, Kabeerdoss J, Ram B, et al. Serum cytokine profile in Asian Indian patients with Takayasu arteritis and its association with disease activity. Open Rheumatol J, 2017, 11: 23-29.
20. Pathadan AP, Tyagi S, Gupta MD, et al. The study of novel inflammatory markers in Takayasu arteritis and its correlation with disease activity. Indian Heart J, 2021, 73(5): 640-643.
21. Sun Y, Kong X, Cui X, et al. The value of interleukin-6 in predicting disease relapse for Takayasu arteritis during 2-year follow-up. Clin Rheumatol, 2020, 39(11): 3417-3425.
22. Noris M, Daina E, Gamba S, et al. Interleukin-6 and RANTES in Takayasu arteritis: a guide for therapeutic decisions? Circulation, 1999, 100(1): 55-60.
23. Alibaz-Oner F, Yentür SP, Saruhan-Direskeneli G, et al. Serum cytokine profiles in Takayasu’s arteritis: search for biomarkers. Clin Exp Rheumatol. 2015, 33(2 Suppl 89): S-32-5.
24. Tamura N, Maejima Y, Tezuka D, et al. Profiles of serum cytokine levels in Takayasu arteritis patients: potential utility as biomarkers for monitoring disease activity. J Cardiol, 2017, 70(3): 278-285.
25. Gao Q, Wu ZY , Yu J, et al. Single-cell RNA sequencing revealed CD14⁺ monocytes increased in patients with Takayasu’s arteritis requiring surgical management. Front Cell Dev Biol, 2021, 9: 761300. doi: 10.3389/fcell.2021.761300.
26. Li J, Wang Y, Wang Y, et al. Association between acute phase reactants, interleukin-6, tumor necrosis factor-α, and disease activity in Takayasu’s arteritis patients. Arthritis Res Ther, 2020, 22(1): 285. doi: 10.1186/s13075-020-02365-y.
27. Maciejewski-Duval A, Comarmond C, Leroyer A, et al. mTOR pathway activation in large vessel vasculitis. J Autoimmun, 2018, 94: 99-109.
28. Rathore U, Thakare DR, Patro P, et al. A systematic review of clinical and preclinical evidences for Janus kinase inhibitors in large vessel vasculitis. Clin Rheumatol, 2022, 41(1): 33-44.
29. Kong X, Wu S, Dai X, et al. A comprehensive profile of chemokines in the peripheral blood and vascular tissue of patients with Takayasu arteritis. Arthritis Res Ther, 2022, 24(1): 49. doi: 10.1186/s13075-022-02740-x.
30. Kong X, Sun Y, Ma L, et al. The critical role of IL-6 in the pathogenesis of Takayasu arteritis. Clin Exp Rheumatol. 2016, 34(3 Suppl 97): S21-S27.
31. Kong X, Ma L, Ji Z, et al. Pro-fibrotic effect of IL-6 via aortic adventitial fibroblasts indicates IL-6 as a treatment target in Takayasu arteritis. Clin Exp Rheumatol. 2018, 36(1): 62-72.
32. Chen R, Sun Y, Cui X, et al. Autophagy promotes aortic adventitial fibrosis via the IL-6/Jak1 signaling pathway in Takayasu’s arteritis. J Autoimmun, 2019, 99: 39-47.
33. 高擎, 吴志远, 李海洋, 等. 单细胞转录组测序在多发性大动脉炎肾动脉病变中的初步探索. 中国医学科学院学报, 2023, 45(1): 80-87.
34. Nishimoto N, Nakahara H, Yoshio-Hoshino N, et al. Successful treatment of a patient with Takayasu arteritis using a humanized anti-interleukin-6 receptor antibody. Arthritis Rheum, 2008, 58(4): 1197-1200.
35. Nakaoka Y, Isobe M, Takei S, et al. Efficacy and safety of tocilizumab in patients with refractory Takayasu arteritis: results from a randomised, double-blind, placebo-controlled, phase 3 trial in Japan (the TAKT study). Ann Rheum Dis, 2018, 77(3): 348-354.
36. Harigai M, Miyamae T, Hashimoto H, et al. A multicentre, large-scale, observational study of tocilizumab in patients with Takayasu arteritis in Japan: The ACT-Bridge Study. Mod Rheumatol, 2022, roac099. doi: 10.1093/mr/roac099.
37. Mekinian A, Saadoun D, Vicaut E, et al. Tocilizumab in treatment-naïve patients with Takayasu arteritis: TOCITAKA French prospective multicenter open-labeled trial. Arthritis Res Ther, 2020, 22(1): 218. doi: 10.1186/s13075-020-02311-y.

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Current status and progress of interleukin-6 in Takayasu arteritis

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