The role of interleukin-17 in the pathogenesis of rheumatoid arthritis

Article

Abstract

Interleukin (IL)-17 (also known as IL-17A), the signature cytokine of the newly described T helper 17 (Th17) cell population, has been implicated in the pathogenesis of numerous autoimmune diseases including rheumatoid arthritis. IL-17 is the founding member of a new subclass of cytokines that have highly proinflammatory properties. Studies in rodents and mammalian cell culture systems, as well as clinical settings, support a role for IL-17 in promoting rheumatoid arthritis. This article discusses the history of the discovery of Th17 cells, the potential mechanisms of action of IL-17 in autoimmunity, and perspectives for IL-17-targeted cytokine therapy.

References and Recommended Reading

  1. 1.
    Mosmann TR, Cherwinski H, Bond MW, et al.: Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 1986, 136:2348–2357.PubMedGoogle Scholar
  2. 2.
    Steinman L: A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nature Med 2007, 13:139–145.PubMedCrossRefGoogle Scholar
  3. 3.
    Murphy CA, Langrish CL, Chen Y, et al.: Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 2003, 198:1951–1957.PubMedCrossRefGoogle Scholar
  4. 4.
    McGeachy MJ, Cua DJ: The link between IL-23 and Th17 cell-mediated immune pathologies. Semin Immunol 2007, 19:372–376.PubMedCrossRefGoogle Scholar
  5. 5.
    Aggarwal S, Ghilardi N, Xie MH, et al.: Interleukin 23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin 17. J Biol Chem 2003, 278:1910–1914.PubMedCrossRefGoogle Scholar
  6. 6.
    Aarvak T, Chabaud M, Miossec P, Natvig JB: IL-17 is produced by some proinflammatory Th1/Th0 cells but not by Th2 cells. J Immunol 1999, 162:1246–1251.PubMedGoogle Scholar
  7. 7.
    Infante-Duarte C, Horton HF, Byrne MC, Kamradt T: Microbial lipopeptides induce the production of IL-17 in Th cells. J Immunol 2000, 165:6107–6115.PubMedGoogle Scholar
  8. 8.
    Park H, Li Z, Yang XO, et al.: A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005, 6:1133–1141.PubMedCrossRefGoogle Scholar
  9. 9.
    Harrington LE, Hatton RD, Mangan PR, et al.: Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 2005, 6:1123–1132.PubMedCrossRefGoogle Scholar
  10. 10.
    McGeachy MJ, Bak-Jensen KS, Chen Y, et al.: TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol 2007, 8:1390–1397.PubMedCrossRefGoogle Scholar
  11. 11.
    Duerr RH, Taylor KD, Brant SR, et al.: A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006, 314:1461–1463.PubMedCrossRefGoogle Scholar
  12. 12.
    Bettelli E, Carrier Y, Gao W, et al.: Reciprocal developmental pathways for the generation of pathogenic effector T(H)17 and regulatory T cells. Nature 2006, 441:235–238.PubMedCrossRefGoogle Scholar
  13. 13.
    Mangan PR, Harrington LE, O’Quinn DB, et al.: Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 2006, 441:231–234.PubMedCrossRefGoogle Scholar
  14. 14.
    Wei G, Wei L, Zhu J, et al.: Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 2009, 30:155–167.PubMedCrossRefGoogle Scholar
  15. 15.
    Lee YK, Turner H, Maynard CL, et al.: Late developmental plasticity in the T helper 17 lineage. Immunity 2009, 30:92–107.PubMedCrossRefGoogle Scholar
  16. 16.
    Lohr J, Knoechel B, Caretto D, Abbas AK: Balance of Th1 and Th17 effector and peripheral regulatory T cells. Microbes Infect 2009, 11:589–593.PubMedCrossRefGoogle Scholar
  17. 17.
    Korn T, Bettelli E, Oukka M, Kuchroo VK: IL-17 and Th17 Cells. Annu Rev Immunol 2009, 27:485–518.PubMedCrossRefGoogle Scholar
  18. 18.
    Wright JF, Guo Y, Quazi A, et al.: Identification of an interleukin 17F/17A heterodimer in activated human CD4+ T cells. J Biol Chem 2007, 282:13447–13455.PubMedCrossRefGoogle Scholar
  19. 19.
    Gaffen SL: Structure and signalling in the IL-17 receptor superfamily. Nat Rev Immunol 2009, 9:556–567.PubMedCrossRefGoogle Scholar
  20. 20.
    Shen F, Gaffen SL: Structure-function relationships in the IL-17 receptor: implications for signal transduction and therapy. Cytokine 2008, 41:92–104.PubMedCrossRefGoogle Scholar
  21. 21.
    Zrioual S, Ecochard R, Tournadre A, et al.: Genome-wide comparison between IL-17A- and IL-17F-induced effects in human rheumatoid arthritis synoviocytes. J Immunol 2009, 182:3112–3120.PubMedCrossRefGoogle Scholar
  22. 22.
    Liang SC, Tan XY, Luxenberg DP, et al.: Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 2006, 203:2271–2279.PubMedCrossRefGoogle Scholar
  23. 23.
    Toh ML, Miossec P: The role of T cells in rheumatoid arthritis: new subsets and new targets. Curr Opin Rheumatol 2007, 19:284–288.PubMedCrossRefGoogle Scholar
  24. 24.
    Lubberts E: IL-17/Th17 targeting: on the road to prevent chronic destructive arthritis? Cytokine 2008, 41:84–91.PubMedCrossRefGoogle Scholar
  25. 25.
    Nakae S, Nambu A, Sudo K, Iwakura Y: Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J Immunol 2003, 171:6173–6177.PubMedGoogle Scholar
  26. 26.
    Nakae S, Saijo S, Horai R, et al.: IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist. Proc Natl Acad Sci U S A 2003, 100:5986–5990.PubMedCrossRefGoogle Scholar
  27. 27.
    Sato K, Suematsu A, Okamoto K, et al.: Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med 2006, 203:2673–2682.PubMedCrossRefGoogle Scholar
  28. 28.
    Shen F, Ruddy MJ, Plamondon P, Gaffen SL: Cytokines link osteoblasts and inflammation: microarray analysis of interleukin-17- and TNF-alpha-induced genes in bone cells. J Leukoc Biol 2005, 77:388–399.PubMedCrossRefGoogle Scholar
  29. 29.
    Gaffen SL, Hajishengallis G: A new inflammatory cytokine on the block: re-thinking periodontal disease and the Th1/Th2 paradigm in the context of Th17 cells and IL-17. J Dent Res 2008, 87:817–828.PubMedCrossRefGoogle Scholar
  30. 30.
    Yu J, Ruddy M, Wong G, et al.: An essential role for IL-17 in preventing pathogen-initiated bone destruction: recruitment of neutrophils to inflamed bone requires IL-17 receptor-dependent signals. Blood 2007, 109:3794–3802.PubMedCrossRefGoogle Scholar
  31. 31.
    Quinn JM, Sims NA, Saleh H, et al.: IL-23 inhibits osteoclastogenesis indirectly through lymphocytes and is required for the maintenance of bone mass in mice. J Immunol 2008, 181:5720–5729.PubMedGoogle Scholar
  32. 32.
    Kotake S, Udagawa N, Takahashi N, et al.: IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest 1999, 103:1345–1352.PubMedCrossRefGoogle Scholar
  33. 33.
    Ziolkowska M, Koc A, Luszczukiewicz G, et al.: High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporin A-sensitive mechanism. J Immunol 2000, 164:2832–2838.PubMedGoogle Scholar
  34. 34.
    Honorati MC, Meliconi R, Pulsatelli L, et al.: High in vivo expression of interleukin-17 receptor in synovial endothelial cells and chondrocytes from arthritis patients. Rheumatology (Oxford) 2001, 40:522–527.CrossRefGoogle Scholar
  35. 35.
    Chabaud M, Fossiez F, Taupin JL, Miossec P: Enhancing effect of IL-17 on IL-1-induced IL-6 and leukemia inhibitory factor production by rheumatoid arthritis synoviocytes and its regulation by Th2 cytokines. J Immunol 1998, 161:409–414.PubMedGoogle Scholar
  36. 36.
    Cai L, Yin JP, Starovasnik MA, et al.: Pathways by which interleukin 17 induces articular cartilage breakdown in vitro and in vivo. Cytokine 2001, 16:10–21.PubMedCrossRefGoogle Scholar
  37. 37.
    Shahrara S, Pickens SR, Dorfleutner A, Pope RM: IL-17 induces monocyte migration in rheumatoid arthritis. J Immunol 2009, 182:3884–3891.PubMedCrossRefGoogle Scholar
  38. 38.
    Kirkham BW, Lassere MN, Edmonds JP, et al.: Synovial membrane cytokine expression is predictive of joint damage progression in rheumatoid arthritis: a two-year prospective study (the DAMAGE study cohort). Arthritis Rheum 2006, 54:1122–1131.PubMedCrossRefGoogle Scholar
  39. 39.
    Yamada H, Nakashima Y, Okazaki K, et al.: Th1 but not Th17 cells predominate in the joints of patients with rheumatoid arthritis. Ann Rheum Dis 2008, 67:1299–1304.PubMedCrossRefGoogle Scholar
  40. 40.
    Scheinecker C, Redlich L, Smolen JS: Cytokines as therapeutic targets: advances and limitations. Immunity 2008, 28:440–444.PubMedCrossRefGoogle Scholar
  41. 41.
    Zaba LC, Cardinale I, Gilleaudeau P, et al.: Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses. J Exp Med 2007, 204:3183–3194.PubMedCrossRefGoogle Scholar
  42. 42.
    Reich K, Yasothan U, Kirkpatrick P: Ustekinumab. Nat Rev Drug Discov 2009, 8:355–356.PubMedCrossRefGoogle Scholar
  43. 43.
    Smolen JS, Beaulieu A, Rubbert-Roth A, et al.: Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet 2008, 371:987–997.PubMedCrossRefGoogle Scholar
  44. 44.
    McInnes IB, Schett G: Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol 2007, 7:429–442.PubMedCrossRefGoogle Scholar
  45. 45.
    Strangfeld A, Listing J: Infection and musculoskeletal conditions: bacterial and opportunistic infections during anti-TNF therapy. Best Pract Res Clin Rheumatol 2006, 20:1181–1195.PubMedCrossRefGoogle Scholar
  46. 46.
    O’Quinn DB, Palmer MT, Lee YK, Weaver CT: Emergence of the Th17 pathway and its role in host defense. Adv Immunol 2008, 99:115–163.PubMedCrossRefGoogle Scholar
  47. 47.
    Conti H, Shen F, Nayyar N, et al.: Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis. J Exp Med 2009, 206:299–311.PubMedCrossRefGoogle Scholar
  48. 48.
    Fischer A: Connecting STAT3, Th17 and human mucosal immunity. Immunol Cell Biol 2008, 86:549–551.PubMedCrossRefGoogle Scholar
  49. 49.
    Freeman AF, Holland SM: The hyper-IgE syndromes. Immunol Allergy Clin North Am 2008, 28:277–291, viii.PubMedCrossRefGoogle Scholar

Copyright information

© Current Medicine Group, LLC 2009

Authors and Affiliations

  1. 1.Department of Medicine, Division of Rheumatology and Clinical ImmunologyUniversity of PittsburghPittsburghUSA

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