Vol 70, No 4 (2019)
Original paper
Published online: 2019-04-02

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The level of IL-35 in the circulation of patients with Graves’ disease

Meng Shuai12, Yan Ni2, Xu Jian2, Shuangtao He2, Jin-an Zhang32
Pubmed: 30938833
Endokrynol Pol 2019;70(4):318-322.


Introduction: The aim of this study was to explore the potential role of IL-35 in Graves’ disease (GD).

Material and methods: A total of 142 GD patients including 80 newly onset patients, 52 refractory patients and 10 remission patients and 70 normal controls (NCs) were recruited. The messenger RNA (mRNA) expressions of P35 and Epstein-Barr-virus-induced gene 3 (Ebi3) were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Serum level of IL-35 was measured by enzyme-linked immunosorbent assay (ELISA).

Results: The expression of IL-35mRNA in new onset GD and refractory GD were both significantly higher than NC. Comparison between remission GD and NC showed no significant difference (p > 0.05). A significant increase of Ebi3mRNA expression was observed in new onset GD compared with remission GD (p = 0.030). The new onset GD showed a tendency for increased expression of serum IL-35 but without significant difference. No correlation between IL-35 expression and clinic parameters was found.

Conclusions: Our preliminary observations indicate that IL-35 and CD4+P35+Ebi3+T cells may be involved in the pathogenesis of GD.

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  1. Eshaghkhani Y, Sanati MH, Nakhjavani M, et al. Disturbed Th1 and Th2 balance in patients with Graves' disease. Minerva Endocrinol. 2016; 41(1): 28–36.
  2. Rapoport B, McLachlan SM. Graves' hyperthyroidism is antibody-mediated but is predominantly a Th1-type cytokine disease. J Clin Endocrinol Metab. 2014; 99(11): 4060–4061.
  3. Shen J, Li Z, Li W, et al. Th1, Th2, and Th17 Cytokine Involvement in Thyroid Associated Ophthalmopathy. Dis Markers. 2015; 2015: 609593.
  4. Bossowski A, Moniuszko M, Idźkowska E, et al. Decreased proportions of CD4 + IL17+/CD4 + CD25 + CD127- and CD4 + IL17+/CD4 + CD25 + CD127 - FoxP3+ T cells in children with autoimmune thyroid diseases (.). Autoimmunity. 2016; 49(5): 320–328.
  5. Lv M, Shen J, Li Z, et al. [Role of Treg/Th17 cells and related cytokines in Graves' ophthalmopathy]. Nan Fang Yi Ke Da Xue Xue Bao. 2014; 34(12): 1809–1813.
  6. Song RH, Yu ZY, Qin Q, et al. Different levels of circulating Th22 cell and its related molecules in Graves' disease and Hashimoto's thyroiditis. Int J Clin Exp Pathol. 2014; 7(7): 4024–4031.
  7. Zhang J, Ren M, Zeng H, et al. Elevated follicular helper T cells and expression of IL-21 in thyroid tissues are involved in the pathogenesis of Graves' disease. Immunol Res. 2015; 62(2): 163–174.
  8. Zhu C, Ma J, Liu Y, et al. Increased frequency of follicular helper T cells in patients with autoimmune thyroid disease. J Clin Endocrinol Metab. 2012; 97(3): 943–950.
  9. Collison LW, Workman CJ, Kuo TT, et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature. 2007; 450(7169): 566–569.
  10. Collison LW, Chaturvedi V, Henderson AL, et al. IL-35-mediated induction of a potent regulatory T cell population. Nat Immunol. 2010; 11(12): 1093–1101.
  11. Egwuagu CE, Yu CR. Interleukin 35-Producing B Cells (i35-Breg): A New Mediator of Regulatory B-Cell Functions in CNS Autoimmune Diseases. Crit Rev Immunol. 2015; 35(1): 49–57.
  12. Fonseca-Camarillo G, Furuzawa-Carballeda J, Yamamoto-Furusho JK. Interleukin 35 (IL-35) and IL-37: Intestinal and peripheral expression by T and B regulatory cells in patients with Inflammatory Bowel Disease. Cytokine. 2015; 75(2): 389–402.
  13. Wang RX, Yu CR, Dambuza IM, et al. Interleukin-35 induces regulatory B cells that suppress autoimmune disease. Nat Med. 2014; 20(6): 633–641.
  14. Collison LW, Delgoffe GM, Guy CS, et al. The composition and signaling of the IL-35 receptor are unconventional. Nat Immunol. 2012; 13(3): 290–299.
  15. Ma Y, Chen L, Xie G, et al. Elevated level of interleukin-35 in colorectal cancer induces conversion of T cells into iTr35 by activating STAT1/STAT3. Oncotarget. 2016; 7(45): 73003–73015.
  16. Niedbala W, Wei XQ, Cai B, et al. IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells. Eur J Immunol. 2007; 37(11): 3021–3029.
  17. Yilmaz H, Cakmak M, Ceydilek B, et al. Role of interlekin-35 as a biomarker in patients with newly diagnosed Hashimoto's thyroiditis. Endocr Regul. 2016; 50(2): 55–61.
  18. Ouyang H, Shi YB, Liu ZC, et al. Decreased interleukin 35 and CD4+EBI3+ T cells in patients with active systemic lupus erythematosus. Am J Med Sci. 2014; 348(2): 156–161.
  19. Li Y, Wang Y, Liu Y, et al. The possible role of the novel cytokines il-35 and il-37 in inflammatory bowel disease. Mediators Inflamm. 2014; 2014: 136329.
  20. Jafarzadeh A, Jamali M, Mahdavi R, et al. Circulating levels of interleukin-35 in patients with multiple sclerosis: evaluation of the influences of FOXP3 gene polymorphism and treatment program. J Mol Neurosci. 2015; 55(4): 891–897.
  21. Kochetkova I, Golden S, Holderness K, et al. IL-35 stimulation of CD39+ regulatory T cells confers protection against collagen II-induced arthritis via the production of IL-10. J Immunol. 2010; 184(12): 7144–7153.
  22. Yasuda T, Okamoto Y, Hamada N, et al. Serum vitamin D levels are decreased in patients without remission of Graves' disease. Endocrine. 2013; 43(1): 230–232.
  23. Workman CJ, Szymczak-Workman AL, Collison LW, et al. The development and function of regulatory T cells. Cell Mol Life Sci. 2009; 66(16): 2603–2622.
  24. Zhou J, Bi M, Fan C, et al. Regulatory T cells but not T helper 17 cells are modulated in an animal model of Graves' hyperthyroidism. Clin Exp Med. 2012; 12(1): 39–46.
  25. Thiolat A, Denys A, Petit M, et al. Interleukin-35 gene therapy exacerbates experimental rheumatoid arthritis in mice. Cytokine. 2014; 69(1): 87–93.
  26. Ye S, Wu J, Zhou L, et al. Interleukin-35: the future of hyperimmune-related diseases? J Interferon Cytokine Res. 2013; 33(6): 285–291.
  27. Kochetkova I, Golden S, Holderness K, et al. IL-35 stimulation of CD39+ regulatory T cells confers protection against collagen II-induced arthritis via the production of IL-10. J Immunol. 2010; 184(12): 7144–7153.