, Volume 27, Issue 5, pp 439–452 | Cite as

The Th17 Pathway as a Therapeutic Target in Rheumatoid Arthritis and Other Autoimmune and Inflammatory Disorders

  • Debbie M. Roeleveld
  • Annemarie E. M. van Nieuwenhuijze
  • Wim B. van den BergEmail author
  • Marije I. Koenders
Leading Article


Production of the pro-inflammatory cytokine interleukin (IL)-17 by Th17 cells and other cells of the immune system protects the host against bacterial and fungal infections, but also promotes the development of rheumatoid arthritis (RA) and other autoimmune and inflammatory disorders. Several biologicals targeting IL-17, the IL-17 receptor, or IL-17-related pathways are being tested in clinical trials, and might ultimately lead to better treatment for patients suffering from various IL-17-mediated disorders. In this review, we provide a clear overview of current knowledge on Th17 cell regulation and the main Th17 effector cytokines in relation to IL-17-mediated conditions, as well as on recent IL-17-related drug developments. We demonstrate that targeting the Th17 pathway is a promising treatment for rheumatoid arthritis and various other autoimmune and inflammatory diseases. However, improvements in technical developments assisting in the identification of patients suffering from IL-17-driven disease are needed to enable the application of tailor-made, personalized medicine.


Rheumatoid Arthritis Psoriasis Rheumatoid Arthritis Patient Th17 Cell Idiopathic Pulmonary Fibrosis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Acknowledgments and Disclosures

The RUNMC research was sponsored by the Innovative Medicines Initiative Joint Undertaking-funded project BTCure (grant number: agreement 115142-2). The authors have no conflicts of interest that are directly relevant to the contents of this article.


  1. 1.
    Moseley TA, Haudenschild DR, Rose L, Reddi AH. Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev. 2003;14(2):155–74 (PubMed: 12651226).PubMedGoogle Scholar
  2. 2.
    Iwakura Y, Ishigame H, Saijo S, Nakae S. Functional specialization of interleukin-17 family members. Immunity. 2011;34(2):149–62 (PubMed: 21349428).PubMedGoogle Scholar
  3. 3.
    Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6(11):1133–41 (PubMed: 1620006).PubMedGoogle Scholar
  4. 4.
    Hueber AJ, Asquith DL, Miller AM, Reilly J, Kerr S, Leipe J, et al. Mast cells express IL-17A in rheumatoid arthritis synovium. J Immunol. 2010;184(7):3336–40 (PubMed: 20200272).PubMedGoogle Scholar
  5. 5.
    Miossec P, Korn T, Kuchroo VK. Interleukin-17 and type 17 helper T cells. N Engl J Med. 2009;361(9):888–98 (PubMed: 19710487).PubMedGoogle Scholar
  6. 6.
    Chabaud M, Durand JM, Buchs N, Fossiez F, Page G, Frappart L, Miossec P. Human interleukin-17: a T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum. 1999;42(5):963–70 (PubMed: 10323452).PubMedGoogle Scholar
  7. 7.
    Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest. 1999;103(9):1345–52 (PubMed: 10225978).PubMedGoogle Scholar
  8. 8.
    Shen H, Xia L, Lu J, Xiao W. Infliximab reduces the frequency of interleukin 17-producing cells and the amounts of interleukin 17 in patients with rheumatoid arthritis. J Investig Med. 2010;58(7):905–8 (PubMed: 20601897).PubMedGoogle Scholar
  9. 9.
    Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem. 2003;278(3):1910–4 (PubMed: 12417590).PubMedGoogle Scholar
  10. 10.
    Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med. 2006;203(12):2673–82 (PubMed: 17088434).PubMedGoogle Scholar
  11. 11.
    Tyagi AM, Srivastava K, Mansoori MN, Trivedi R, Chattopadhyay N, Singh D. Estrogen deficiency induces the differentiation of IL-17 secreting Th17 cells: a new candidate in the pathogenesis of osteoporosis. PLoS ONE. 2012;7(9):e44552 (PubMed: 22970248).PubMedGoogle Scholar
  12. 12.
    Van Bezooijen RL, Van Der Wee-Pals L, Papapoulos SE, Löwik CW. Interleukin 17 synergises with tumour necrosis factor alpha to induce cartilage destruction in vitro. Ann Rheum Dis. 2002;61(10):870–6 (PubMed: 12228154).PubMedGoogle Scholar
  13. 13.
    Koenders MI, Marijnissen RJ, Devesa I, Lubberts E, Joosten LA, Roth J, et al. Tumor necrosis factor-IL-17 interplay induces S100A8, interleukin-1β, and matrix metalloproteinases, and drives irreversible cartilage destruction in murine arthritis. Arthritis Rheum. 2011;63(8):2329–39 (PubMed: 21520013).PubMedGoogle Scholar
  14. 14.
    Lubberts E, van den Bersselaar L, Oppers-Walgreen B, Schwarzenberger P, Coenen-de Roo CJ, Kolls JK, et al. IL-17 promotes bone erosion in murine collagen-induced arthritis through loss of the receptor activator of NF-kappa B ligand/osteoprotegerin balance. J Immunol. 2003;170(5):2655–62 (PubMed: 12594294).PubMedGoogle Scholar
  15. 15.
    Koenders MI, Lubberts E, Oppers-Walgreen B, van den Bersselaar L, Helsen MM, Di Padova FE, et al. Blocking of interleukin-17 during reactivation of experimental arthritis prevents joint inflammation and bone erosion by decreasing RANKL and interleukin-1. Am J Pathol. 2005;167(1):141–9 (PubMed: 15972960).PubMedGoogle Scholar
  16. 16.
    Zwerina K, Koenders M, Hueber A, Marijnissen RJ, Baum W, Heiland GR, et al. Anti IL-17A therapy inhibits bone loss in TNF-α-mediated murine arthritis by modulation of the T-cell balance. Eur J Immunol. 2012;42(2):413–23 (PubMed: 22101928).PubMedGoogle Scholar
  17. 17.
    Lubberts E, Koenders MI, Oppers-Walgreen B, van den Bersselaar L, Coenen-de Roo CJ, Joosten LA, et al. Treatment with a neutralizing anti-murine interleukin-17 antibody after the onset of collagen-induced arthritis reduces joint inflammation, cartilage destruction, and bone erosion. Arthritis Rheum. 2004;50(2):650–9 (PubMed: 14872510).PubMedGoogle Scholar
  18. 18.
    Kim KW, Kim HR, Park JY, Park JS, Oh HJ, Woo YJ, et al. Interleukin-22 promotes osteoclastogenesis in rheumatoid arthritis through induction of RANKL in human synovial fibroblasts. Arthritis Rheum. 2012;64(4):1015–23 (PubMed: 22034096).PubMedGoogle Scholar
  19. 19.
    Kwok SK, Cho ML, Park MK, Oh HJ, Park JS, Her YM, et al. Interleukin-21 promotes osteoclastogenesis in humans with rheumatoid arthritis and in mice with collagen-induced arthritis. Arthritis Rheum. 2012;64(3):740–51 (PubMed: 21968544).PubMedGoogle Scholar
  20. 20.
    Young DA, Hegen M, Ma HL, Whitters MJ, Albert LM, Lowe L, et al. Blockade of the interleukin-21/interleukin-21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis. Arthritis Rheum. 2007;56(4):1152–63 (PubMed: 17393408).PubMedGoogle Scholar
  21. 21.
    Pelletier M, Bouchard A, Girard D. In vivo and in vitro roles of IL-21 in inflammation. J Immunol. 2004;173(12):7521–30 (PubMed: 15585879).PubMedGoogle Scholar
  22. 22.
    Peluso I, Fantini MC, Fina D, Caruso R, Boirivant M, MacDonald TT, et al. IL-21 counteracts the regulatory T cell-mediated suppression of human CD4+ T lymphocytes. J Immunol. 2007;178(2):732–9 (PubMed: 17202333).PubMedGoogle Scholar
  23. 23.
    Jang E, Cho SH, Park H, Paik DJ, Kim JM, Youn J. A positive feedback loop of IL-21 signaling provoked by homeostatic CD4+ CD25- T cell expansion is essential for the development of arthritis in autoimmune K/BxN mice. J Immunol. 2009;182(8):4649–56 (PubMed: 19342640).PubMedGoogle Scholar
  24. 24.
    Marijnissen RJ, Koenders MI, Smeets RL, Stappers MH, Nickerson-Nutter C, Joosten LA, et al. Increased expression of interleukin-22 by synovial Th17 cells during late stages of murine experimental arthritis is controlled by interleukin-1 and enhances bone degradation. Arthritis Rheum. 2011;63(10):2939–48 (PubMed: 21618207).PubMedGoogle Scholar
  25. 25.
    Geboes L, Dumoutier L, Kelchtermans H, Schurgers E, Mitera T, Renauld JC, Matthys P. Proinflammatory role of the Th17 cytokine interleukin-22 in collagen-induced arthritis in C57BL/6 mice. Arthritis Rheum. 2009;60(2):390–5 (PubMed: 19180498).PubMedGoogle Scholar
  26. 26.
    Leipe J, Schramm MA, Grunke M, Baeuerle M, Dechant C, Nigg AP, et al. Interleukin 22 serum levels are associated with radiographic progression in rheumatoid arthritis. Ann Rheum Dis. 2011;70(8):1453–7 (PubMed: 21593004).PubMedGoogle Scholar
  27. 27.
    Santarlasci V, Maggi L, Capone M, Frosali F, Querci V, De Palma R, et al. TGF-beta indirectly favors the development of human Th17 cells by inhibiting Th1 cells. Eur J Immunol. 2009;39(1):207–15 (PubMed: 19130583).PubMedGoogle Scholar
  28. 28.
    Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F. Interleukins 1 beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol. 2007;8(9):942–9 (PubMed: 17676045).PubMedGoogle Scholar
  29. 29.
    Wilson NJ, Boniface K, Chan JR, McKenzie BS, Blumenschein WM, Mattson JD, et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol. 2007;8(9):950–7 (PubMed: 17676044).PubMedGoogle Scholar
  30. 30.
    Manel N, Unutmaz D, Littman DR. The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol. 2008;9(6):641–9 (PubMed: 18454151).PubMedGoogle Scholar
  31. 31.
    Volpe E, Servant N, Zollinger R, Bogiatzi SI, Hupé P, Barillot E, Soumelis V. A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat Immunol. 2008;9(6):650–7 (PubMed: 18454150).PubMedGoogle Scholar
  32. 32.
    Yang L, Anderson DE, Baecher-Allan C, Hastings WD, Bettelli E, Oukka M, et al. IL-21 and TGF-beta are required for differentiation of human T(H) 17 cells. Nature. 2008;454(7202):350–2 (PubMed: 18469800).PubMedGoogle Scholar
  33. 33.
    Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441(7090):235–8 (PubMed: 16648838).PubMedGoogle Scholar
  34. 34.
    Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 2006;24(2):179–89 (PubMed: 16473830).PubMedGoogle Scholar
  35. 35.
    Gutcher I, Donkor MK, Ma Q, Rudensky AY, Flavel RA, Li MO. Autocrine transforming growth factor-β1 promotes in vivo Th17 cell differentiation. Immunity. 2011;34(3):396–408 (PubMed: 21435587).PubMedGoogle Scholar
  36. 36.
    Veldhoen M, Hocking RJ, Flavell RA, Stockinger B. Signals mediated by transforming growth factor-beta initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease. Nat Immunol. 2006;7(11):1151–6 (PubMed: 16998492).PubMedGoogle Scholar
  37. 37.
    Martinez GJ, Zhang Z, Reynolds JM, Tanaka S, Chung Y, Liu T, et al. Smad2 positively regulates the generation of Th17 cells. J Biol Chem. 2010;285(38):29030–43 (PubMed: 20667820).Google Scholar
  38. 38.
    Qin H, Wang L, Feng T, Elson CO, Niyongere SA, Lee SJ, et al. TGF-beta promotes Th17 cell development through inhibition of SOCS3. J Immunol. 2009;183(1):97–105 (PubMed: 19535626).PubMedGoogle Scholar
  39. 39.
    Lee WW, Kang SW, Choi J, Lee SH, Shah K, Eynon EE, et al. Regulating human Th17 cells via differential expression of IL-1 receptor. Blood. 2010;115(3):530–40 (PubMed: 19965648).PubMedGoogle Scholar
  40. 40.
    Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC, Elson CO, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature. 2006;441(7090):231–4 (PubMed: 16648837).PubMedGoogle Scholar
  41. 41.
    McGeachy MJ, Chen Y, Tato CM, Laurence A, Joyce-Shaikh B, Blumenschein WM, et al. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol. 2009;10(3):314–24 (PubMed: 19182808).PubMedGoogle Scholar
  42. 42.
    Nurieva R, Yang XO, Martinez G, Zhang Y, Panopoulos AD, Ma L, et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature. 2007;448(7152):480–3 (PubMed: 17581589).PubMedGoogle Scholar
  43. 43.
    Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, et al. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol. 2007;8(9):967–74 (PubMed: 17581537).PubMedGoogle Scholar
  44. 44.
    Chen Z, Laurence A, Kanno Y, Pacher-Zavisin M, Zhu BM, Tato C, et al. Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc Natl Acad Sci USA. 2006;103(21):8137–42 (PubMed: 16698929).PubMedGoogle Scholar
  45. 45.
    Hirota K, Duarte JH, Veldhoen M, Hornsby E, Li Y, Cua DJ, et al. Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol. 2011;12(3):255–63 (PubMed: 21278737).PubMedGoogle Scholar
  46. 46.
    Lexberg MH, Taubner A, Albrecht I, Lepenies I, Richter A, Kamradt T, et al. IFN-γ and IL-12 synergize to convert in vivo generated Th17 into Th1/Th17 cells. Eur J Immunol. 2010;40(11):3017–27 (PubMed: 21061434).PubMedGoogle Scholar
  47. 47.
    Wang W, Shao S, Jiao Z, Guo M, Xu H, Wang S. The Th17/Treg imbalance and cytokine environment in peripheral blood of patients with rheumatoid arthritis. Rheumatol Int. 2012;32(4):887–93 (PubMed: 21221592).PubMedGoogle Scholar
  48. 48.
    McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365(23):2205–19 (PubMed: 22150039).PubMedGoogle Scholar
  49. 49.
    Colmegna I, Ohata BR, Menard HA. Current understanding of rheumatoid arthritis therapy. Clin Pharmacol Ther. 2012;91(4):607–20 (PubMed: 22357455).PubMedGoogle Scholar
  50. 50.
    Aaltonen KJ, Virkki LM, Malmivaara A, Konttinen YT, Nordström DC, Blom M. Systematic review and meta-analysis of the efficacy and safety of existing TNF blocking agents in treatment of rheumatoid arthritis. PLoS ONE. 2012;7(1):e30275 (PubMed: 22272322).PubMedGoogle Scholar
  51. 51.
    Aerts NE, De Knop KJ, Leysen J, Ebo DG, Bridts CH, Weyler JJ, et al. Increased IL-17 production by peripheral T helper cells after tumour necrosis factor blockade in rheumatoid arthritis is accompanied by inhibition of migration-associated chemokine receptor expression. Rheumatology (Oxford). 2010;49(12):2264–72 (PubMed: 20724433).Google Scholar
  52. 52.
    Chen DY, Chen YM, Chen HH, Hsieh CW, Lin CC, Lan JL. Increasing levels of circulating Th17 cells and interleukin-17 in rheumatoid arthritis patients with an inadequate response to anti-TNF-α therapy. Arthritis Res Ther. 2011;13(4):R126 (PubMed: 21801431).PubMedGoogle Scholar
  53. 53.
    Koenders MI, Lubberts E, van de Loo FA, Oppers-Walgreen B, van den Bersselaar L, Helsen MM, et al. Interleukin-17 acts independently of TNF-alpha under arthritic conditions. J Immunol. 2006;176(10):6262–9 (PubMed: 16670337).PubMedGoogle Scholar
  54. 54.
    Yago T, Nanke Y, Kawamoto M, Yamanaka H, Kotake S. Tacrolimus potently inhibits human osteoclastogenesis induced by IL-17 from human monocytes alone and suppresses human Th17 differentiation. Cytokine. 2012;59(2):252–7 (PubMed: 22579702).PubMedGoogle Scholar
  55. 55.
    Genovese MC, Van den Bosch F, Roberson SA, Bojin S, Biagini IM, Ryan P, Sloan-Lancaster J. LY2439821, a humanized anti-interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I randomized, double-blind, placebo-controlled, proof-of-concept study. Arthritis Rheum. 2010;62(4):929–39 (PubMed: 20131262).PubMedGoogle Scholar
  56. 56.
    National Library of Medicine. (Internet). Bethesda (MD): National Library of Medicine (US). 1 Jan 1993. Identifier NCT00966875, a study in patients with rheumatoid arthritis; 25 Aug 2009 (cited 5 Dec 2012); (about 6 screens). Available from:
  57. 57.
    National Library of Medicine. (Internet). Bethesda (MD): National Library of Medicine (US). 1 Jan 1993. Identifier NCT01426789, a biomarker study of secukinumab in rheumatoid arthritis patients; 12 Aug 2011 (cited 5 Dec 2012); (about 3 screens). Available from:
  58. 58.
    Koenders MI, Marijnissen RJ, Joosten LA, Abdollahi-Roodsaz S, Di Padova FE, van de Loo FA, et al. T cell lessons from the rheumatoid arthritis synovium SCID mouse model: CD3-rich synovium lacks response to CTLA-4Ig but is successfully treated by interleukin-17 neutralization. Arthritis Rheum. 2012;64(6):1762–70 (PubMed: 22213107).PubMedGoogle Scholar
  59. 59.
    National Library of Medicine. (Internet). Bethesda (MD): National Library of Medicine (US). 1 Jan 1993. Identifier NCT01640938, study to evaluate the long term efficacy, safety and tolerability of secukinumab in patients with rheumatoid arthritis; 12 July 2012 (cited 5 Dec 2012); (about 4 screens). Available from:
  60. 60.
    National Library of Medicine. (Internet). Bethesda (MD): National Library of Medicine (US). 1 Jan 1993. Identifier NCT01059448, safety and efficacy of AMG 827 in subjects with RA; 28 Jan 2010 (cited 5 Dec 2012); (about 5 screens). Available from:
  61. 61.
    Papp KA, Leonardi C, Menter A, Ortonne JP, Krueger JG, Kricorian G, et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl J Med. 2012;366(13):1181–9 (PubMed: 22455412).PubMedGoogle Scholar
  62. 62.
    Tanaka Y, Maeshima Y, Yamaoka K. In vitro and in vivo analysis of a JAK inhibitor in rheumatoid arthritis. Ann Rheum Dis. 2012;71(Suppl 2):i70–4 (PubMed: 22460142).PubMedGoogle Scholar
  63. 63.
    Nakagawa R, Yoshida H, Asakawa M, Tamiya T, Inoue N, Morita R, et al. Pyridone 6, a pan-JAK inhibitor, ameliorates allergic skin inflammation of NC/Nga mice via suppression of Th2 and enhancement of Th17. J Immunol. 2011;187(9):4611–20 (PubMed: 21957150).PubMedGoogle Scholar
  64. 64.
    Yoshida H, Kimura A, Fukaya T, Sekiya T, Morita R, Shichita T, et al. Low dose CP-690,550 (tofacitinib), a pan-JAK inhibitor, accelerates the onset of experimental autoimmune encephalomyelitis by potentiating Th17 differentiation. Biochem Biophys Res Commun. 2012;418(2):234–40 (PubMed: 22252297).PubMedGoogle Scholar
  65. 65.
    Mori T, Miyamoto T, Yoshida H, Asakawa M, Kawasumi M, Kobayashi T, et al. IL-1β and TNF-α-initiated IL-6-STAT3 pathway is critical in mediating inflammatory cytokines and RANKL expression in inflammatory arthritis. Int Immunol. 2011;23(11):701–12.PubMedGoogle Scholar
  66. 66.
    van de Veerdonk FL, Lauwerys B, Marijnissen RJ, Timmermans K, Di Padova F, Koenders MI, et al. The anti-CD20 antibody rituximab reduces the Th17 cell response. Arthritis Rheum. 2011;63(6):1507–16 (PubMed: 21400475).PubMedGoogle Scholar
  67. 67.
    Huh JR, Leung MW, Huang P, Ryan DA, Krout MR, Malapaka RR, et al. Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORγt activity. Nature. 2011;472(7344):486–90 (PubMed: 21441909).PubMedGoogle Scholar
  68. 68.
    Fujita-Sato S, Ito S, Isobe T, Ohyama T, Wakabayashi K, Morishita K, et al. Structural basis of digoxin that antagonizes RORgamma t receptor activity and suppresses Th17 cell differentiation and interleukin (IL)-17 production. J Biol Chem. 2011;286(36):31409–17 (PubMed: 21733845).PubMedGoogle Scholar
  69. 69.
    Solt LA, Kumar N, Nuhant P, Wang Y, Lauer JL, Liu J, et al. Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature. 2011;472(7344):491–4 (PubMed: 21499262).PubMedGoogle Scholar
  70. 70.
    Krausz S, Boumans MJ, Gerlag DM, Lufkin J, van Kuijk AW, Bakker A, et al. Brief report: a phase IIa, randomized, double-blind, placebo-controlled trial of apilimod mesylate, an interleukin-12/interleukin-23 inhibitor, in patients with rheumatoid arthritis. Arthritis Rheum. 2012;64(6):1750–5 (PubMed: 22170479).PubMedGoogle Scholar
  71. 71.
    Duvallet E, Semerano L, Assier E, Falgarone G, Boissier MC. Interleukin-23: a key cytokine in inflammatory diseases. Ann Med. 2011;43(7):503–11 (PubMed: 21585245).PubMedGoogle Scholar
  72. 72.
    Garber K. Anti-IL-17 mAbs herald new options in psoriasis. Nat Biotechnol. 2012;30(6):475–7 (PubMed: 22678368).PubMedGoogle Scholar
  73. 73.
    McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007;7(6):429–42 (PubMed: 17525752).PubMedGoogle Scholar
  74. 74.
    Buch MH, Bingham SJ, Seto Y, McGonagle D, Bejarano V, White J, Emery P. Lack of response to anakinra in rheumatoid arthritis following failure of tumor necrosis factor alpha blockade. Arthritis Rheum. 2004;50(3):725–8 (PubMed: 15022311).PubMedGoogle Scholar
  75. 75.
    Lu ZY, Brochier J, Wijdenes J, Brailly H, Bataille R, Klein B. High amounts of circulating interleukin (IL)-6 in the form of monomeric immune complexes during anti-IL-6 therapy. Towards a new methodology for measuring overall cytokine production in human in vivo. Eur J Immunol. 1992;22(11):2819–24 (PubMed: 1425909).PubMedGoogle Scholar
  76. 76.
    Fujimoto M, Serada S, Mihara M, Uchiyama Y, Yoshida H, Koike N. Interleukin-6 blockade suppresses autoimmune arthritis in mice by the inhibition of inflammatory Th17 responses. Arthritis Rheum. 2008;58(12):3710–9 (PubMed: 19035481).PubMedGoogle Scholar
  77. 77.
    Samson M, Audia S, Janikashvili N, Ciudad M, Trad M, Fraszczak J, et al. Brief report: inhibition of interleukin-6 function corrects Th17/Treg cell imbalance in patients with rheumatoid arthritis. Arthritis Rheum. 2012;64(8):2499–503 (PubMed: 22488116).PubMedGoogle Scholar
  78. 78.
    Nishimoto N, Terao K, Mima T, Nakahara H, Takagi N, Kakehi T. Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood. 2008;112(10):3959–64 (PubMed: 18784373).PubMedGoogle Scholar
  79. 79.
    Emery P, Keystone E, Tony HP, Cantagrel A, van Vollenhoven R, Sanchez A, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biological: results from a 24-week multicentre randomized placebo-controlled trial. Ann Rheum Dis. 2008;67(11):1516–23 (PubMed: 18625622).PubMedGoogle Scholar
  80. 80.
    Jones SA, Scheller J, Rose-John S. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest. 2011;121(9):3375–83 (PubMed: 21881215).PubMedGoogle Scholar
  81. 81.
    Dumont N, Arteaga CL. Targeting the TGF beta signaling network in human neoplasia. Cancer Cell. 2003;3(6):531–6 (PubMed: 12842082).PubMedGoogle Scholar
  82. 82.
    Lonning S, Mannick J, McPherson JM. Antibody targeting of TGF-β in cancer patients. Curr Pharm Biotechnol. 2011;12(12):2176–89 (PubMed: 21619535).PubMedGoogle Scholar
  83. 83.
    Smith AL, Robin TP, Ford HL. Molecular pathways: targeting the TGF-β pathway for cancer therapy. Clin Cancer Res. 2012;18(17):4514–21 (PubMed: 22711703).PubMedGoogle Scholar
  84. 84.
    Caproni M, Antiga E, Melani L, Volpi W, Del Bianco E, Fabbri P. Serum levels of IL-17 and IL-22 are reduced by etanercept, but not by acitretin, in patients with psoriasis: a randomized-controlled trial. J Clin Immunol. 2009;29(2):210–4 (PubMed: 18763027).PubMedGoogle Scholar
  85. 85.
    Hegyi Z, Zwicker S, Bureik D, Peric M, Koglin S, Batycka-Baran A, et al. Vitamin D analog calcipotriol suppresses the Th17 cytokine-induced proinflammatory S100 “alarmins” psoriasin (S100A7) and koebnerisin (S100A15) in psoriasis. J Invest Dermatol. 2012;132(5):1416–24 (PubMed: 22402441).PubMedGoogle Scholar
  86. 86.
    Liang SC, Tan XY, Luxenberg DP, Karim R, Dunussi-Joannopoulos K, Collins M, Fouser LA. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med. 2006;203(10):2271–9 (PubMed: 16982811).PubMedGoogle Scholar
  87. 87.
    Nograles KE, Zaba LC, Guttman-Yassky E, Fuentes-Duculan J, Suárez-Fariñas M, Cardinale I, et al. Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways. Br J Dermatol. 2008;159(5):1092–102 (PubMed: 18684158).PubMedGoogle Scholar
  88. 88.
    Krueger JG, Fretzin S, Suárez-Fariñas M, Haslett PA, Phipps KM, Cameron GS, et al. IL-17A is essential for cell activation and inflammatory gene circuits in subjects with psoriasis. J Allergy Clin Immunol. 2012;130(1):145–54.e9 (PubMed: 22677045).PubMedGoogle Scholar
  89. 89.
    Leonardi C, Matheson R, Zachariae C, Cameron G, Li L, Edson-Heredia E, et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med. 2012;366(13):1190–9 (PubMed: 22455413).PubMedGoogle Scholar
  90. 90.
    National Library of Medicine. (Internet). Bethesda (MD): National Library of Medicine (US). 1 Jan 1993. Identifier NCT01646177, a study in participants with moderate to severe psoriasis (UNCOVER-3); 18 July 2012 (cited 2 Dec 2012); (about 4 screens). Available from:
  91. 91.
    Papp KA, Langley RG, Sigurgeirsson B, Abe M, Baker DR, Konno P, et al. Efficacy and safety of secukinumab in the treatment of moderate to severe plaque psoriasis: a randomized, double-blind, placebo-controlled phase II dose-ranging study. Br J Dermatol. 2013;168(2):412–21 (PubMed: 23106107).Google Scholar
  92. 92.
    Rich P, Sigurgeirsson B, Thaci DP, Ortonne JP, Paul C, Schopf RE, et al. Secukinumab induction and maintenance therapy in moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled, phase II regimen-finding study. Br J Dermatol. 2012; Epub ahead of print (PubMed: 23020120).Google Scholar
  93. 93.
    National Library of Medicine. (Internet). Bethesda (MD): National Library of Medicine (US). 1 Jan 1993. Identifier NCT01539213, distribution of secukinumab (AIN457) into dermal interstitial fluid after a single subcutaneous administration of 300 mg (OFM ISF); 23 Dec 2011 (cited 2 Dec 2012); (about 4 screens). Available from:
  94. 94.
    National Library of Medicine. (Internet). Bethesda (MD): National Library of Medicine (US). 1 Jan 1993. Identifier NCT01537432, multiple-dose regimen study to assess effect of 12 months of secukinumab treatment on skin response and biomarkers in psoriasis patients; 17 Feb 2012 (cited 2 Dec 2012); (about 4 screens). Available from:
  95. 95.
    National Library of Medicine. (Internet). Bethesda (MD): National Library of Medicine (US). 1 Jan 1993. Identifier NCT01406938, efficacy and safety of subcutaneous secukinumab (AIN457) for moderate to severe chronic plaque-type psoriasis assessing different doses and dose regimens (SCULPTURE); 12 July 2011 (cited 2 Dec 2012); (about 4 screens). Available from:
  96. 96.
    National Library of Medicine. (Internet). Bethesda (MD): National Library of Medicine (US). 1 Jan 1993. Identifier NCT01636687, judging the efficacy of secukinumab in patients with psoriasis using autoiNjector: a clinical trial evaluating treatment results (JUNCTURE); 6 July 2012 (cited 2 Dec 2012); (about 4 screens). Available from:
  97. 97.
    National Library of Medicine. (Internet). Bethesda (MD): National Library of Medicine (US). 1 Jan 1993. Identifier NCT01365455, efficacy and safety of subcutaneous secukinumab for moderate to severe chronic plaque-type psoriasis for up to 1 year (ERASURE); 1 June 2011 (cited 2 Dec 2012); (about 4 screens). Available from:
  98. 98.
    National Library of Medicine. (Internet). Bethesda (MD): National Library of Medicine (US). 1 Jan 1993. Identifier NCT01544595, extension study of secukinumab prefilled syringes in subjects with moderate to severe chronic plaque-type psoriasis completing preceding psoriasis phase III studies with secukinumab; 28 Feb 2012 (cited 2 Dec 2012); (about 4 screens). Available from:
  99. 99.
    National Library of Medicine. (Internet). Bethesda (MD): National Library of Medicine (US). 1993 Jan 1. Identifier NCT01708603, study of efficacy and safety of brodalumab compared with placebo and ustekinumab in moderate to severe plaque psoriasis subjects (AMAGINE-2); 12 Sep 2012 (cited 2 Dec 2012); (about 5 screens). Available from:
  100. 100.
    National Library of Medicine. (Internet). Bethesda (MD): National Library of Medicine (US). 1 Jan 1993. Identifier NCT01708590, study of efficacy, safety, and withdrawal and retreatment with brodalumab in moderate to severe plaque psoriasis subjects (AMAGINE-1); 10 Sep 2012 (cited 2 Dec 2012); (about 4 screens). Available from:
  101. 101.
    Bullens DM, Truyen E, Coteur L, Dilissen E, Hellings PW, Dupont LJ, Ceuppens JL. IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx? Respir Res. 2006;7:135 (PubMed: 17083726).PubMedGoogle Scholar
  102. 102.
    Bazzi MD, Sultan MA, Al Tassan N, Alanzi M, Al-Amri A, Al-Hajjaj MS, et al. Interleukin 17A and F and asthma in Saudi Arabia: gene polymorphisms and protein levels. J Investig Allergol Clin Immunol. 2011;21(7):551–5 (PubMed: 22312940).PubMedGoogle Scholar
  103. 103.
    Agache I, Ciobanu C, Agache C, Anghel M. Increased serum IL-17 is an independent risk factor for severe asthma. Respir Med. 2010;104(8):1131–7 (PubMed: 20338742).PubMedGoogle Scholar
  104. 104.
    Chakir J, Shannon J, Molet S, Fukakusa M, Elias J, Laviolette M, et al. Airway remodeling-associated mediators in moderate to severe asthma: effect of steroids on TGF-beta, IL-11, IL-17, and type I and type III collagen expression. J Allergy Clin Immunol. 2003;111(6):1293–8 (PubMed: 12789232).PubMedGoogle Scholar
  105. 105.
    Shi YH, Shi GC, Wan HY, Jiang LH, Ai XY, Zhu HX, et al. Coexistence of Th1/Th2 and Th17/Treg imbalances in patients with allergic asthma. Chin Med J (Engl). 2011;124(13):1951–6 (PubMed: 22088452).Google Scholar
  106. 106.
    Bajoriuniene I, Malakauskas K, Lavinskiene S, Jeroch J, Gasiuniene E, Vitkauskiene A, Sakalauskas R. Response of peripheral blood Th17 cells to inhaled Dermatophagoides pteronyssinus in patients with allergic rhinitis and asthma. Lung. 2012;190(5):487–95 (PubMed: 22990520).PubMedGoogle Scholar
  107. 107.
    Zhao Y, Yang J, Gao YD, Guo W. Th17 immunity in patients with allergic asthma. Int Arch Allergy Immunol. 2010;151(4):297–307 (PubMed: 19844129).PubMedGoogle Scholar
  108. 108.
    Molet S, Hamid Q, Davoine F, Nutku E, Taha R, Pagé N, et al. IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines. J Allergy Clin Immunol. 2001;108(3):430–8 (PubMed: 11544464).PubMedGoogle Scholar
  109. 109.
    Wang Q, Li H, Yao Y, Xia D, Zhou J. The overexpression of heparin-binding epidermal growth factor is responsible for Th17-induced airway remodeling in an experimental asthma model. J Immunol. 2010;185(2):834–41 (PubMed: 20530256).PubMedGoogle Scholar
  110. 110.
    Wei B, Zhang H, Li L, Li M, Shang Y. T helper 17 cells and regulatory T-cell imbalance in paediatric patients with asthma. J Int Med Res. 2011;39(4):1293–305 (PubMed: 21986131).PubMedGoogle Scholar
  111. 111.
    Durrant DM, Gaffen SL, Riesenfeld EP, Irvin CG, Metzger DW. Development of allergen-induced airway inflammation in the absence of T-bet regulation is dependent on IL-17. J Immunol. 2009;183(8):5293–300 (PubMed: 19783683).PubMedGoogle Scholar
  112. 112.
    Guan Q, Ma Y, Aboud L, Weiss CR, Qing G, Warrington RJ, Peng Z. Targeting IL-23 by employing a p40 peptide-based vaccine ameliorates murine allergic skin and airway inflammation. Clin Exp Allergy. 2012;42(9):1397–405 (PubMed: 22925326).PubMedGoogle Scholar
  113. 113.
    Hölltä V, Klemetti P, Sipponen T, Westerholm-Ormio M, Kociubinski G, Salo H, et al. IL-23/IL-17 immunity as a hallmark of Crohn’s disease. Inflamm Bowel Dis. 2008;14(9):1175–84 (PubMed: 18512248).Google Scholar
  114. 114.
    Fujino S, Andoh A, Bamba S, Ogawa A, Hata K, Araki Y, et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut. 2003;52(1):65–70 (PubMed: 12477762).PubMedGoogle Scholar
  115. 115.
    Veny M, Esteller M, Ricart E, Piqué JM, Panés J, Salas A. Late Crohn’s disease patients present an increase in peripheral Th17 cells and cytokine production compared with early patients. Aliment Pharmacol Ther. 2010;31(5):561–72 (PubMed: 19958311).PubMedGoogle Scholar
  116. 116.
    Hölltä V, Sipponen T, Westerholm-Ormio M, Salo HM, Kolho KL, Färkkilä M, et al. In Crohn’s disease, anti-TNF-α treatment changes the balance between mucosal IL-17, FOXP3, and CD4 cells. ISRN Gastroenterol. 2012;505432. (PubMed: 22778976).Google Scholar
  117. 117.
    Fonseca-Camarillo G, Mendivil-Rangel E, Furuzawa-Carballeda J, Yamamoto-Furusho JK. Interleukin 17 gene and protein expression are increased in patients with ulcerative colitis. Inflamm Bowel Dis. 2011;17(10):E135–6 (PubMed: 21761512).PubMedGoogle Scholar
  118. 118.
    Kobayashi T, Okamoto S, Hisamatsu T, Kamada N, Chinen H, Saito R, et al. IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn’s disease. Gut. 2008;57(12):1682–9 (PubMed: 18653729).PubMedGoogle Scholar
  119. 119.
    Nielsen OH, Kirman I, Rüdiger N, Hendel J, Vainer B. Upregulation of interleukin-12 and -17 in active inflammatory bowel disease. Scand J Gastroenterol. 2003;38(2):180–5 (PubMed: 12678335).PubMedGoogle Scholar
  120. 120.
    Arisawa T, Tahara T, Shibata T, Nagasaka M, Nakamura M, Kimaya Y, et al. The influence of polymorphisms of interleukin-17A and interleukin-17F genes on the susceptibility to ulcerative colitis. J Clin Immunol. 2008;28(1):44–9 (PubMed: 17828618).PubMedGoogle Scholar
  121. 121.
    Stumhofer JS, Laurence A, Wilson EH, Huang E, Tato CM, Johnson LM, et al. Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat Immunol. 2006;7(9):937–45 (PubMed: 1690616).PubMedGoogle Scholar
  122. 122.
    El-behi M, Ciric B, Yu S, Zhang GX, Fitzgerald DC, Rostami A. Differential effect of IL-27 on developing versus committed Th17 cells. J Immunol. 2009;183(8):4957–67 (PubMed: 19786534).PubMedGoogle Scholar
  123. 123.
    Sasaoka T, Ito M, Yamashita J, Nakajima K, Tanaka I, Narita M, et al. Treatment with IL-27 attenuates experimental colitis through the suppression of the development of IL-17-producing T helper cells. Am J Physiol Gastrointest Liver Physiol. 2011;300(4):G568–76 (PubMed: 21193526).PubMedGoogle Scholar
  124. 124.
    Hueber W, Sands BE, Lewitzky S, Vandemeulebroecke M, Reinisch W, Higgins PD, et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomized, double-blind placebo-controlled trial. Gut. 2012;61(12):1693–700 (PubMed: 22595313).PubMedGoogle Scholar
  125. 125.
    Herrlinger KR, Diculescu M, Fellermann K, Hartmann H, Howaldt S, Nikolov R, et al. Efficacy, safety and tolerability of vidofludimus in patients with inflammatory bowel disease: the ENTRANCE study. J Crohns Colitis. 2012; Epub ahead of print. (PubMed: 23078909).Google Scholar
  126. 126.
    Chen P, Baldeviano GC, Ligons DL, Talor MV, Barin JG, Rose NR, Cihakova D. Susceptibility to autoimmune myocarditis is associated with intrinsic differences in CD4(+) T cells. Clin Exp Immunol. 2012;169(2):79–88 (PubMed: 22774982).PubMedGoogle Scholar
  127. 127.
    Durelli L, Conti L, Clerico M, Boselli D, Contessa G, Ripellino P, et al. T-helper 17 cells expand in multiple sclerosis and are inhibited by interferon-beta. Ann Neurol. 2009;65(5):499–509 (PubMed: 19475668).PubMedGoogle Scholar
  128. 128.
    Kürtüncü M, Tüzün E, Türkoğlu R, Petek-Balcı B, Içöz S, Pehlivan M, et al. Effect of short-term interferon-β treatment on cytokines in multiple sclerosis: significant modulation of IL-17 and IL-23. Cytokine. 2012;59(2):400–2 (PubMed: 22652415).PubMedGoogle Scholar
  129. 129.
    Wen SR, Liu GJ, Feng RN, Gong FC, Zhong H, Duan SR, Bi S. Increased levels of IL-23 and osteopontin in serum and cerebrospinal fluid of multiple sclerosis patients. J Neuroimmunol. 2012;244(1–2):94–6 (PubMed: 22329905).PubMedGoogle Scholar
  130. 130.
    Matusevicius D, Kivisäkk P, He B, Kostulas N, Ozenci V, Fredrikson S, Link H. Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mult Scler. 1999;5(2):101–4 (PubMed: 10335518).PubMedGoogle Scholar
  131. 131.
    Xu L, Zhang T, Liu Z, Li Q, Xu Z, Ren T. Critical role of Th17 cells in development of autoimmune hemolytic anemia. Exp Hematol. 2012;40(12):994–1004 (PubMed: 22960264).PubMedGoogle Scholar
  132. 132.
    Chan YR, Chen K, Duncan SR, Lathrop KL, Latoche JD, Logar AJ, et al. Patients with cystic fibrosis have inducible IL-17(+) IL-22(+) memory cells in lung draining lymph nodes. J Allergy Clin Immunol. 2013;131(4):1117–1129 (PubMed: 22795370).Google Scholar
  133. 133.
    Alunno A, Bistoni O, Bartoloni E, Caterbi S, Bigerna B, Tabarrini A, et al. IL-17-producing CD4− CD8− T cells are expanded in the peripheral blood, infiltrate salivary glands and are resistant to corticosteroids in patients with primary Sjogren’s syndrome. Ann Rheum Dis. 2012;72(2):286–92 (PubMed: 22904262).Google Scholar
  134. 134.
    Tu E, Ang DK, Bellingham SA, Hogan TV, Teng MW, Smyth MJ, et al. Both IFN-γ and IL-17 are required for the development of severe autoimmune gastritis. Eur J Immunol. 2012;42(10):2574–83 (PubMed: 22777705).PubMedGoogle Scholar
  135. 135.
    Wilson MS, Madala SK, Ramalingam TR, Gochuico BR, Rosas IO, Cheever AW, Wynn TA. Bleomycin and IL-1beta-mediated pulmonary fibrosis is IL-17A dependent. J Exp Med. 2010;207(3):535–52 (PubMed: 20176803).PubMedGoogle Scholar
  136. 136.
    He D, Li H, Yusuf N, Elmets CA, Athar M, Katiyar SK, Xu H. IL-17 mediated inflammation promotes tumor growth and progression in the skin. PLoS ONE. 2012;7(2):e32126 (PubMed: 22359662).PubMedGoogle Scholar
  137. 137.
    Kim SE, Yoon JS, Kim KH, Lee SY. Increased serum interleukin-17 in Graves’ ophthalmopathy. Graefes Arch Clin Exp Ophthalmol. 2012;250(10):1521–6 (PubMed: 22752189).PubMedGoogle Scholar
  138. 138.
    Gelderblom M, Weymar A, Bernreuther C, Velden J, Arunachalam P, Steinbach K, et al. Neutralization of the IL-17 axis diminishes neutrophil invasion and protects from ischemic stroke. Blood. 2012;120(18):3793–802 (PubMed: 22976954).PubMedGoogle Scholar
  139. 139.
    Kostulas N, Pelidou SH, Kivisäkk P, Kostulas V, Link H. Increased IL-1beta, IL-8, and IL-17 mRNA expression in blood mononuclear cells observed in a prospective ischemic stroke study. Stroke. 1999;30(10):2174–9 (PubMed: 10512924).PubMedGoogle Scholar
  140. 140.
    Shichita T, Sugiyama Y, Ooboshi H, Sugimori H, Nakagawa R, Takada I, et al. Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury. Nat Med. 2009;15(8):946–50 (PubMed: 19648929).PubMedGoogle Scholar
  141. 141.
    Li GZ, Zhong D, Yang LM, Sun B, Zhong ZH, Yin YH, et al. Expression of interleukin-17 in ischemic brain tissue. Scand J Immunol. 2005;62(5):481–6 PubMed: 16305645).PubMedGoogle Scholar
  142. 142.
    Yan X, Shichita T, Katsumata Y, Matsuhashi T, Ito H, Ito K, et al. Deleterious effect of the IL-23/IL-17A axis and γδT cells on left ventricular remodelling after myocardial infarction. J Am Heart Assoc. 2012;1(5):e0044078 (PubMed: 23316306).Google Scholar
  143. 143.
    van de Veerdonk FL, Marijnissen RJ, Kullberg BJ, Koenen HJ, Cheng SC, Joosten I, et al. The macrophage mannose receptor induced IL-17 in response to Candida albicans. Cell Host Microbe. 2009;5(4):329–40 (PubMed: 19380112).Google Scholar
  144. 144.
    Dobritsa SV, Kuok IT, Nguyen H, Webster JC, Spragg AM, Morley T, Carr GJ. Development of a high-throughput cell-based assay for identification of IL-17 inhibitors. J Biomol Screen. 2013;18(1):75–84 (PubMed: 22983163).Google Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  • Debbie M. Roeleveld
    • 1
  • Annemarie E. M. van Nieuwenhuijze
    • 1
  • Wim B. van den Berg
    • 1
    Email author
  • Marije I. Koenders
    • 1
  1. 1.Radboud University Nijmegen Medical CentreNijmegenThe Netherlands

Personalised recommendations