REVIEW
Interleukin-35 regulates the balance of Th17 and Treg responses during the pathogenesis of connective tissue diseases
Di Wang,
Ling Lei,
Di Wang
Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
Search for more papers by this authorCorresponding Author
Ling Lei
Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
Correspondence
Ling Lei, Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China.
Email: [email protected]
Search for more papers by this authorDi Wang,
Ling Lei,
Di Wang
Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
Search for more papers by this authorCorresponding Author
Ling Lei
Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
Correspondence
Ling Lei, Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China.
Email: [email protected]
Search for more papers by this authorAbstract
Interleukin (IL)-35 belongs to the IL-12 cytokine family and is a heterodimer of the p35 and Epstein-Barr virus-induced gene 3 (EBI3) subunits. Functionally, IL-35 can promote the proliferation and activation of regulatory T cells (Tregs) and suppress the function of T helper 17 (Th17) cells and other inflammatory cells to inhibit immune responses. In recent years, an abnormal IL-35 expression causing a Th17/Treg imbalance has been associated with the development and progression of several connective tissue diseases (CTDs), such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), dermatomyositis (DM)/polymyositis (PM), and primary Sjögren’s syndrome (pSS). Here, we review the role of IL-35 in regulating the balance of Th17/Treg responses in different types of CTDs and provide new insights into the role of IL-35 in these diseases.
CONFLICT OF INTEREST
Neither of the authors have any conflicts of interest. There has been no interest or relationship with pharmaceutical agencies within the past 36 months.
REFERENCES
- 1Sokolov AV, Shmidt AA, Lomakin YA. B cell regulation in autoimmune diseases. Acta Naturae. 2018; 10(3): 11-22.
- 2Tedder TF, Leonard WJ. Autoimmunity: regulatory B cells–IL-35 and IL-21 regulate the regulators. Nat Rev Rheumatol. 2014; 10(8): 452-453.
- 3Collison 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.
- 4Collison LW, Workman CJ, Kuo TT, et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature. 2007; 450(7169): 566-569.
- 5Whitehead GS, Wilson RH, Nakano K, Burch LH, Nakano H, Cook DN. IL-35 production by inducible costimulator (ICOS)-positive regulatory T cells reverses established IL-17-dependent allergic airways disease. J Allergy Clin Immunol. 2012; 129(1): 207-215.e1-e5.. https://doi.org/10.1016/j.jaci.2011.08.009
- 6Wirtz S, Billmeier U, McHedlidze T, Blumberg RS, Neurath MF. Interleukin-35 mediates mucosal immune responses that protect against T-cell-dependent colitis. Gastroenterology. 2011; 141(5): 1875-1886.
- 7Wang RX, Yu CR, Dambuza IM, et al. Interleukin-35 induces regulatory B cells that suppress autoimmune disease. Nat Med. 2014; 20(6): 633-641.
- 8Ye Z, Jiang Y, Sun D, Zhong W, Zhao L, Jiang Z. The plasma interleukin (IL)-35 level and frequency of circulating IL-35(+) regulatory B cells are decreased in a cohort of chinese patients with new-onset systemic lupus erythematosus. Sci Rep. 2019; 9(1): 13210. https://doi.org/10.1038/s41598-019-49748-z
- 9Krishnamurthy A, Joshua V, Haj Hensvold A, et al. Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated autoantibody-mediated bone loss. Ann Rheum Dis. 2016; 75(4): 721-729.
- 10Wigerblad G, Bas DB, Fernades-Cerqueira C, et al. Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism. Ann Rheum Dis. 2016; 75(4): 730-738.
- 11Schett G, Gravallese E. Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment. Nat Rev Rheumatol. 2012; 8(11): 656-664.
- 12Noack M, Miossec P. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev. 2014; 13(6): 668-677.
- 13Samson M, Audia S, Janikashvili N, et al. Brief report: inhibition of interleukin-6 function corrects Th17/Treg cell imbalance in patients with rheumatoid arthritis. Arthritis Rheum. 2012; 64(8): 2499-2503.
- 14Niu Q, Cai B, Huang ZC, Shi YY, Wang LL. Disturbed Th17/Treg balance in patients with rheumatoid arthritis. Rheumatol Int. 2012; 32(9): 2731-2736.
- 15Kawashiri SY, Kawakami A, Okada A, et al. CD4+CD25(high)CD127(low/-) Treg cell frequency from peripheral blood correlates with disease activity in patients with rheumatoid arthritis. J Rheumatol. 2011; 38(12): 2517-2521.
- 16Bystrom J, Clanchy FI, Taher TE, et al. TNFα in the regulation of Treg and Th17 cells in rheumatoid arthritis and other autoimmune inflammatory diseases. Cytokine. 2018; 101: 4-13.
- 17Lubberts E, Koenders MI, van den Berg WB. The role of T-cell interleukin-17 in conducting destructive arthritis: lessons from animal models. Arthritis Res Ther. 2005; 7(1): 29-37.
- 18Jin S, Chen H, Li Y, et al. Maresin 1 improves the Treg/Th17 imbalance in rheumatoid arthritis through miR-21. Ann Rheum Dis. 2018; 77(11): 1644-1652.
- 19Lubberts E. The IL-23-IL-17 axis in inflammatory arthritis. Nat Rev Rheumatol. 2015; 11(7): 415-429.
- 20Gaffen SL, Jain R, Garg AV, Cua DJ. The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat Rev Immunol. 2014; 14(9): 585-600.
- 21Prakken B, Ellen W, van Wijk F. Editorial: quality or quantity? unraveling the role of treg cells in rheumatoid arthritis. Arthritis Rheum. 2013; 65(3): 552-554.
- 22Mauri C, Bosma A. Immune regulatory function of B cells. Annu Rev Immunol. 2012; 30: 221-241.
- 23Sakkas LI. Regulatory B cells in autoimmune rheumatic diseases. Mediterr J Rheumatol. 2017; 28(2): 75-79.
- 24Ma L, Liu B, Jiang Z, Jiang Y. Reduced numbers of regulatory B cells are negatively correlated with disease activity in patients with new-onset rheumatoid arthritis. Clin Rheumatol. 2014; 33(2): 187-195.
- 25Flores-Borja F, Bosma A, Ng D, et al. CD19+CD24hiCD38hi B cells maintain regulatory T cells while limiting TH1 and TH17 differentiation. Sci Transl Med. 2013; 5(173): 173ra23. https://doi.org/10.1126/scitranslmed.3005407
- 26Ray A, Basu S, Williams CB, Salzman NH, Dittel BN. A novel IL-10–independent regulatory role for B cells in suppressing autoimmunity by maintenance of regulatory T cells via GITR ligand. J Immunol. 2012; 188(7): 3188-3198.
- 27Li Y, Yuan L, Jiang S, et al. Interleukin-35 stimulates tumor necrosis factor-α activated osteoblasts differentiation through Wnt/β-catenin signaling pathway in rheumatoid arthritis. Int Immunopharmacol. 2019; 75: 105810.
- 28Peng M, Wang Y, Qiang L, et al. Interleukin-35 inhibits TNF-α-induced osteoclastogenesis and promotes apoptosis via shifting the activation from TNF receptor-associated death domain (TRADD)-TRAF2 to TRADD-Fas-associated death domain by JAK1/STAT1. Front Immunol. 2018; 9: 1417.
- 29Iranshahi N, Assar S, Amiri SM, Zafari P, Fekri A, Taghadosi M. Decreased gene expression of Epstein-Barr virus-induced gene 3 (EBI-3) may contribute to the pathogenesis of rheumatoid arthritis. Immunol Invest. 2019; 48(4): 367-377.
- 30Nakano S, Morimoto S, Suzuki S, et al. Immunoregulatory role of IL-35 in T cells of patients with rheumatoid arthritis. Rheumatology (Oxford, England). 2015; 54(8): 1498-1506.
- 31Kochetkova I, Golden S, Holderness K, Callis G, Pascual DW. 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.
- 32Niedbala 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.
- 33Jiang S, Li Y, Lin T, et al. IL-35 inhibits angiogenesis through VEGF/Ang2/Tie2 pathway in rheumatoid arthritis. Cell Physiol Biochem. 2016; 40(5): 1105-1116.
- 34Li Y, Yao L, Liu S, et al. Elevated serum IL-35 levels in rheumatoid arthritis are associated with disease activity. J Investig Med. 2019; 67(3): 707-710.
- 35Šenolt L, Šumová B, Jandová R, et al. Interleukin 35 synovial fluid levels are associated with disease activity of rheumatoid arthritis. PLoS One. 2015; 10(7):e0132674.
- 36Filková M, Vernerová Z, Hulejová H, et al. Pro-inflammatory effects of interleukin-35 in rheumatoid arthritis. Cytokine. 2015; 73(1): 36-43.
- 37Thiolat A, Denys A, Petit M, et al. Interleukin-35 gene therapy exacerbates experimental rheumatoid arthritis in mice. Cytokine. 2014; 69(1): 87-93.
- 38Yin L, Ge Y, Yang H, et al. The clinical utility of serum IL-35 in patients with polymyositis and dermatomyositis. Clin Rheumatol. 2016; 35(11): 2715-2721.
- 39Ma K, Du W, Wang X, et al. Multiple functions of B cells in the pathogenesis of systemic lupus erythematosus. Int J Mol Sci. 2019; 20(23): 6021. https://doi.org/10.3390/ijms20236021
- 40Xing Q, Wang B, Su H, Cui J, Li J. Elevated Th17 cells are accompanied by FoxP3+ Treg cells decrease in patients with lupus nephritis. Rheumatol Int. 2012; 32(4): 949-958.
- 41Kleczynska W, Jakiela B, Plutecka H, Milewski M, Sanak M, Musial J. Imbalance between Th17 and regulatory T-cells in systemic lupus erythematosus. Folia Histochem Cytobiol. 2011; 49(4): 646-653.
- 42Yang J, Chu Y, Yang X, et al. Th17 and natural Treg cell population dynamics in systemic lupus erythematosus. Arthritis Rheum. 2009; 60(5): 1472-1483.
- 43Scheinecker C, Bonelli M, Smolen JS. Pathogenetic aspects of systemic lupus erythematosus with an emphasis on regulatory T cells. J Autoimmun. 2010; 35(3): 269-275.
- 44Comte D, Karampetsou MP, Tsokos GC. T cells as a therapeutic target in SLE. Lupus. 2015; 24(4-5): 351-363.
- 45Ouyang 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.
- 46He D, Liu M, Liu B. Interleukin-35 as a new biomarker of renal involvement in lupus nephritis patients. Tohoku J Exp Med. 2018; 244(4): 263-270.
- 47Hagiwara Z, Wong CK, LeeDong J, Chu M, Klinman DK. Remission of systemic lupus erythematosus disease activity with regulatory cytokine interleukin (IL)-35 in Murphy Roths Large (MRL)/lpr mice.. Clin Exp Immuno. 2015; 181(2): 253-266.
- 48Qiu F, Song L, Yang N, Li X. Glucocorticoid downregulates expression of IL-12 family cytokines in systemic lupus erythematosus patients. Lupus. 2013; 22(10): 1011-1016.
- 49Cai Z, Wong CK, Kam NW, et al. Aberrant expression of regulatory cytokine IL-35 in patients with systemic lupus erythematosus. Lupus. 2015; 24(12): 1257-1266.
- 50Sakkas LI, Chikanza IC, Platsoucas CD. Mechanisms of Disease: the role of immune cells in the pathogenesis of systemic sclerosis. Nat Clin Pract Rheumatol. 2006; 2(12): 679-685.
- 51Abraham DJ, Varga J. Scleroderma: from cell and molecular mechanisms to disease models. Trends Immunol. 2005; 26(11): 587-595.
- 52Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med. 2009; 360(19): 1989-2003.
- 53Fenoglio D, Bernuzzi F, Battaglia F, et al. Th17 and regulatory T lymphocytes in primary biliary cirrhosis and systemic sclerosis as models of autoimmune fibrotic diseases. Autoimmun Rev. 2012; 12(2): 300-304.
- 54Truchetet ME, Brembilla NC, Montanari E, Allanore Y, Chizzolini C. Increased frequency of circulating Th22 in addition to Th17 and Th2 lymphocytes in systemic sclerosis: association with interstitial lung disease. Arthritis Res Ther. 2011; 13(5): R166. https://doi.org/10.1186/ar3486
- 55Rodríguez-Reyna TS, Furuzawa-Carballeda J, Cabiedes J, et al. Th17 peripheral cells are increased in diffuse cutaneous systemic sclerosis compared with limited illness: a cross-sectional study. Rheumatol Int. 2012; 32(9): 2653-2660.
- 56Nakashima T, Jinnin M, Yamane K, et al. Impaired IL-17 signaling pathway contributes to the increased collagen expression in scleroderma fibroblasts. J Immunol. 2012; 188(8): 3573-3583.
- 57Krasimirova E, Velikova T, Ivanova-Todorova E, et al. Treg/Th17 cell balance and phytohaemagglutinin activation of T lymphocytes in peripheral blood of systemic sclerosis patients. World J Exp Med. 2017; 7(3): 84-96.
- 58Fuschiotti P. CD8+ T cells in systemic sclerosis. Immunol Res. 2011; 50(2-3): 188-194.
- 59Klein M, Schmalzing M, Almanzar G, et al. Contribution of CD8+ T cells to inflammatory cytokine production in systemic sclerosis (SSc). Autoimmunity. 2016; 49(8): 532-546.
- 60Antiga E, Quaglino P, Bellandi S, et al. Regulatory T cells in the skin lesions and blood of patients with systemic sclerosis and morphoea. Br J Dermatol. 2010; 162(5): 1056-1063.
- 61Kudo H, Wang Z, Jinnin M, et al. EBI3 downregulation contributes to type I collagen overexpression in scleroderma skin. J Immunol. 2015; 195(8): 3565-3573.
- 62Tomcik M, Zerr P, Palumbo-Zerr K, et al. Interleukin-35 is upregulated in systemic sclerosis and its serum levels are associated with early disease. Rheumatology. 2015; 54(12): 2273-2282.
- 63Yayla ME, Torgutalp M, Okatan İE, et al. Serum interleukin 35 levels in systemic sclerosis and relationship with clinical features. J Clin Rheumatol. 2020; 26(3): 83-86.
- 64Dantas AT, Gonçalves SM, Pereira MC, et al. Increased IL-35 serum levels in systemic sclerosis and association with pulmonary interstitial involvement. Clin Rheumatol. 2015; 34(9): 1621-1625.
- 65Tang J, Lei L, Pan J, Zhao C, Wen J. Higher levels of serum interleukin-35 are associated with the severity of pulmonary fibrosis and Th2 responses in patients with systemic sclerosis. Rheumatol Int. 2018; 38(8): 1511-1519.
- 66Sakkas LI, Mavropoulos A, Perricone C, Bogdanos DP. IL-35: a new immunomodulator in autoimmune rheumatic diseases. Immunol Res. 2018; 66(3): 305-312.
- 67Goebels N, Michaelis D, Engelhardt M, et al. Differential expression of perforin in muscle-infiltrating T cells in polymyositis and dermatomyositis. J Clin Investig. 1996; 97(12): 2905-2910.
- 68Feng M, Guo H, Zhang C, et al. Absolute reduction of regulatory T cells and regulatory effect of short-term and low-dose IL-2 in polymyositis or dermatomyositis. Int Immunopharmacol. 2019; 77: 105912. https://doi.org/10.1016/j.intimp.2019.105912
- 69Kao AH, Lacomis D, Lucas M, Fertig N, Oddis CV. Anti-signal recognition particle autoantibody in patients with and patients without idiopathic inflammatory myopathy. Arthritis Rheum. 2004; 50(1): 209-215.
- 70Jiang Q, Li Y, Xia L, Shen H, Lu J. Interleukin-35: a serological biomarker for patients with polymyositis/dermatomyositis. J Interferon Cytokine Res. 2019; 39(11): 720-725.
- 71Guo J, Gu M, Zhang W, Liu Y, Qian C, Deng A. Aberrant IL-35 levels in patients with primary Sjogren's syndrome. Scand J Immunol. 2018; 88(5):e12718. https://doi.org/10.1111/sji.12718
- 72Katsifis GE, Moutsopoulos NM, Wahl SM. T lymphocytes in Sjögren's syndrome: contributors to and regulators of pathophysiology. Clin Rev Allergy Immunol. 2007; 32(3): 252-264.
- 73Alunno A, Petrillo MG, Nocentini G, et al. Characterization of a new regulatory CD4+ T cell subset in primary Sjögren's syndrome. Rheumatology (Oxford, England). 2013; 52(8): 1387-1396.
- 74Luo J, Ming B, Zhang C, et al. IL-2 inhibition of Th17 generation rather than induction of treg cells is impaired in primary Sjögren's syndrome patients. Front Immunol. 2018; 9: 1755.
- 75Littman DR, Rudensky AY. Th17 and regulatory T cells in mediating and restraining inflammation. Cell. 2010; 140(6): 845-858.
- 76Liu C, Guan Z, Zhao L, Song Y, Wang H. Elevated level of circulating CD4(+)Helios(+)FoxP3(+) cells in primary Sjogren's syndrome patients. Mod Rheumatol. 2017; 27(4): 630-637.
- 77Fogel O, Rivière E, Seror R, et al. Role of the IL-12/IL-35 balance in patients with Sjögren syndrome. J Allergy Clin Immunol. 2018; 142(1): 258-268.e5.
- 78Lin W, Jin L, Chen H, et al. B cell subsets and dysfunction of regulatory B cells in IgG4-related diseases and primary Sjögren's syndrome: the similarities and differences. Arthritis Res Ther. 2014; 16(3): R118.
- 79Han M, Li Y, Liu S, et al. Elevation of serum IL-35 in patients with primary Sjögren's syndrome. J Interferon Cytokine Res. 2018; 38(10): 452-456.
- 80Hamzaoui K, Borhani Haghighi A, Ghorbel IB, Houman H. RORC and Foxp3 axis in cerebrospinal fluid of patients with neuro-Behçet's disease. J Neuroimmunol. 2011; 233(1-2): 249-253.
- 81Na SY, Park MJ, Park S, Lee ES. Up-regulation of Th17 and related cytokines in Behçet's disease corresponding to disease activity. Clin Exp Rheumatol. 2013; 31(3 Suppl 77): 32-40.
- 82Geri G, Terrier B, Rosenzwajg M, et al. Critical role of IL-21 in modulating TH17 and regulatory T cells in Behçet disease. J Allergy Clin Immunol. 2011; 128(3): 655-664.
- 83Sonmez C, Yucel AA, Yesil TH, et al. Correlation between IL-17A/F, IL-23, IL-35 and IL-12/-23 (p40) levels in peripheral blood lymphocyte cultures and disease activity in Behcet's patients. Clin Rheumatol. 2018; 37(10): 2797-2804.
- 84Yong C, Dan L, Chenhong L, Yan S, Jianfei C, Jianlong G. [Efficacy and safety of metformin for Behcet's disease and its effect on Treg/Th17 balance: a single-blinded, before-after study]. Nan fang yi ke da xue xue bao = J South Med Univ. 2019; 39(2): 127-133.
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