Skip to main content

Advertisement

Log in

Cytokines in rheumatoid arthritis

  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

Rheumatoid arthritis (RA) is a chronic disease characterized by synovial inflammation that leads to the destruction of cartilage and bone. In the last decade, there was a lot of successful research in the field of cytokine expression and regulation. It has become clear that pro- and antiinflammatory cytokines, derived predominantely from cells of macrophage lineage, play a major role in the initiation and perpetuation of the chronic inflammatory process in the RA synovial membrane. Monokines are abundant in rheumatoid synovial tissue, whereas low amounts of lymphokines are found. The involvement of pro-inflammatory cytokines, particularly interleukin (IL)-1 and tumor necrosis factor-alpha, in the pathogenesis of RA is well accepted. Recent data provide evidence that the pro-inflammatory cytokine IL-18 plays a crucial role in the development and sustenance of inflammatory joint diseases. There also appears to be a compensatory anti-inflammatory response in RA synovial membrane. It has become clear in the last few years that T cell-derived cytokines expressed preferentially by Th1 cells contribute to joint destruction and inflammation in RA. However, products from Th2 cells may be protective.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Tak PP, Smeets TJ, Daha MR, et al.: Analysis of the synovial cellular infiltrate in early rheumatoid synovial tissue in relation to disease activity. Arthritis Rheum 1997, 40:217–225.

    Article  PubMed  CAS  Google Scholar 

  2. Kraan MC, Patel DD, Haringman JJ, et al.: The development of clinical signs of rheumatoid synovial inflammation is associated with increased synthesis of the chemokine CXCL8 (interleukin-8). Arthritis Res 2001, 3:65–71.

    Article  PubMed  CAS  Google Scholar 

  3. van den Berg WB: Anti-cytokine therapy in chronic destructive arthritis. Arthritis Res 2001, 3:18–26.

    Article  PubMed  Google Scholar 

  4. Tak PP, Bresnihan B: The pathogenesis and prevention of joint damage in rheumatoid arthritis: advances from synovial biopsy and tissue analysis. Arthritis Rheum 2000, 43:2619–2633.

    Article  PubMed  CAS  Google Scholar 

  5. Smeets TJ, Dolhain RJ, Breedveld FC, Tak PP: Analysis of the cellular infiltrates and expression of cytokines in synovial tissue from patients with rheumatoid arthritis and reactive arthritis. J Pathol 1998, 186:75–81.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  7. Szekanecz Z, Strieter RM, Kunkel SL, Koch AE: Chemokines in rheumatoid arthritis. Springer Semin Immunopathol 1998, 20:115–132.

    Article  PubMed  CAS  Google Scholar 

  8. Maini RN, Elliott M, Brennan FM, Williams RO, Feldmann M:TNF blockade in rheumatoid arthritis: implications for therapy and pathogenesis. APMIS 1997, 105:257–263.

    Article  PubMed  CAS  Google Scholar 

  9. Carteron NL: Cytokines in rheumatoid arthritis: trials and tribulations. Mol Med Today 2000, 6:315–323.

    Article  PubMed  CAS  Google Scholar 

  10. Ulfgren AK, Grondal L, Lindblad S, et al.: Interindividual and intra-articular variation of proinflammatory cytokines in patients with rheumatoid arthritis: potential implications for treatment. Ann Rheum Dis 2000, 59:439–447.

    Article  PubMed  CAS  Google Scholar 

  11. Arend WP: Cytokine imbalance in the pathogenesis of rheumatoid arthritis: the role of interleukin-1 receptor antagonist. Semin Arthritis Rheum 2001, 30:1–6.

    Article  PubMed  CAS  Google Scholar 

  12. Firestein GS, Boyle DL, Yu C, et al.: Synovial interleukin-1 receptor antagonist and interleukin-1 balance in rheumatoid arthritis. Arthritis Rheum 1994, 37:644–652.

    Article  PubMed  CAS  Google Scholar 

  13. Williams RO, Feldmann M, Maini RN: Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. Proc Natl Acad Sci U S A 1992, 89:9784–9788.

    Article  PubMed  CAS  Google Scholar 

  14. Thorbecke GJ, Shah R, Leu CH, et al.: Involvement of endogenous tumor necrosis factor alpha and transforming growth factor beta during induction of collagen type II arthritis in mice. Proc Natl Acad Sci U S A 1992, 89:7375–7379.

    Article  PubMed  CAS  Google Scholar 

  15. Keffer J, Probert L, Cazlaris H, et al.: Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J 1991, 10:4025–4031.

    PubMed  CAS  Google Scholar 

  16. Probert L, Plows D, Kontogeorgos G, Kollias G: The type I interleukin-1 receptor acts in series with tumor necrosis factor (TNF) to induce arthritis in TNF-transgenic mice. Eur J Immunol 1995, 25:1794–1797.

    Article  PubMed  CAS  Google Scholar 

  17. van de Loo AA,van den Berg WB: Effects of murine recombinant interleukin 1 on synovial joints in mice: measurement of patellar cartilage metabolism and joint inflammation. Ann Rheum Dis 1990, 49:238–245.

    Article  PubMed  Google Scholar 

  18. Niki Y, Yamada H, Seki S, et al.: Macrophage- and neutrophildominant arthritis in human IL-1 alpha transgenic mice. J Clin Invest 2001, 107:1127–1135.

    PubMed  CAS  Google Scholar 

  19. Luster AD: Chemokines—chemotactic cytokines that mediate inflammation. N Engl J Med 1998, 338:436–445.

    Article  PubMed  CAS  Google Scholar 

  20. Muller-Ladner U, Roberts CR, Franklin BN, et al.: Human IL- 1Ra gene transfer into human synovial fibroblasts is chondroprotective. J Immunol 1997, 158:3492–3498.

    PubMed  CAS  Google Scholar 

  21. Maini R, St Clair EW, Breedveld F, et al.: Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 1999, 354:1932–1939.

    Article  PubMed  CAS  Google Scholar 

  22. Bathon JM, Martin RW, Fleischmann RM, et al.: A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000, 343:1586–1593.

    Article  PubMed  CAS  Google Scholar 

  23. Feldmann M, Maini RN: Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol 2001, 19:163–196. This review provides a nice overview of inhibitors of tumor necrosis factor-alpha in clinical use and their mechanism of action.

    Article  PubMed  CAS  Google Scholar 

  24. Bresnihan B: The safety and efficacy of interleukin-1 receptor antagonist in the treatment of rheumatoid arthritis. Semin Arthritis Rheum 2001, 30:17–20.

    Article  PubMed  CAS  Google Scholar 

  25. Dayer JM, Feige U, Edwards CK 3rd, Burger D: Anti-interleukin- 1 therapy in rheumatic diseases. Curr Opin Rheumatol 2001, 13:170–176.

    Article  PubMed  CAS  Google Scholar 

  26. Alonzi T, Fattori E, Lazzaro D, et al.: Interleukin 6 is required for the development of collagen-induced arthritis. J Exp Med 1998, 187:461–468.

    Article  PubMed  CAS  Google Scholar 

  27. van de Loo FA, Kuiper S, van Enckevort FH, Arntz OJ,van den Berg WB: Interleukin-6 reduces cartilage destruction during experimental arthritis: a study in interleukin-6-deficient mice. Am J Pathol 1997, 151:177–191.

    PubMed  Google Scholar 

  28. Ernst M, Inglese M, Waring P, et al.: Defective gp130-mediated signal transducer and activator of transcription (STAT) signaling results in degenerative joint disease, gastrointestinal ulceration, and failure of uterine implantation. J Exp Med 2001, 194:189–203.

    Article  PubMed  CAS  Google Scholar 

  29. Taylor PC, Williams RO, Maini RN: Immunotherapy for rheumatoid arthritis. Curr Opin Immunol 2001, 13:611–616.

    Article  PubMed  CAS  Google Scholar 

  30. Nishimoto N, Maede K, Kuritani T, et al.: Safety and efficacy of repetitive treatment with humanized anti-interleukin-6 receptor antibody (MRA) in rheumatoid arthritis [abstract]. Arthritis Rheum 2001, 44:S84.

    Google Scholar 

  31. Morita Y, Yamamura M, Nishida K, et al.: Expression of interleukin-12 in synovial tissue from patients with rheumatoid arthritis. Arthritis Rheum 1998, 41:306–314.

    Article  PubMed  CAS  Google Scholar 

  32. Malfait AM, Butler DM, Presky DH, et al.: Blockade of IL-12 during the induction of collagen-induced arthritis (CIA) markedly attenuates the severity of the arthritis. Clin Exp Immunol 1998, 111:377–383.

    Article  PubMed  CAS  Google Scholar 

  33. McIntyre KW, Shuster DJ, Gillooly KM, et al.: Reduced incidence and severity of collagen-induced arthritis in interleukin-12-deficient mice. Eur J Immunol 1996, 26:2933–2938.

    Article  PubMed  CAS  Google Scholar 

  34. Nakajima A, Seroogy CM, Sandora MR, et al.: Antigen-specific T cell-mediated gene therapy in collagen-induced arthritis. J Clin Invest 2001, 107:1293–1301.

    PubMed  CAS  Google Scholar 

  35. Joosten LA, Lubberts E, Helsen MM,van den Berg WB: Dual role of IL-12 in early and late stages of murine collagen type II arthritis. J Immunol 1997, 159:4094–4102.

    PubMed  CAS  Google Scholar 

  36. Fehniger TA, Caligiuri MA: Interleukin 15: biology and relevance to human disease. Blood 2001, 97:14–32.

    Article  PubMed  CAS  Google Scholar 

  37. Thurkow EW,van der Heijden IM, Breedveld FC, et al.:Increased expression of IL-15 in the synovium of patients with rheumatoid arthritis compared with patients with Yersinia-induced arthritis and osteoarthritis. J Pathol 1997, 181:444–450.

    Article  PubMed  CAS  Google Scholar 

  38. McInnes IB, al-Mughales J, Field M, et al.: The role of interleukin-15 in T-cell migration and activation in rheumatoid arthritis. Nat Med 1996, 2:175–182.

    Article  PubMed  CAS  Google Scholar 

  39. Ziolkowska M, Koc A, Luszczykiewicz 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.

    PubMed  CAS  Google Scholar 

  40. McInnes IB, Leung BP, Sturrock RD, Field M, Liew FY:Interleukin-15 mediates T cell-dependent regulation of tumor necrosis factor-alpha production in rheumatoid arthritis. Nat Med 1997, 3:189–195.

    Article  PubMed  CAS  Google Scholar 

  41. Harada S, Yamamura M, Okamoto H, et al.: Production of interleukin-7 and interleukin-15 by fibroblast-like synoviocytes from patients with rheumatoid arthritis. Arthritis Rheum 1999, 42:1508–1516.

    Article  PubMed  CAS  Google Scholar 

  42. Ruchatz H, Leung BP, Wei XQ, McInnes IB, Liew FY: Soluble IL- 15 receptor alpha-chain administration prevents murine collagen-induced arthritis: a role for IL-15 in development of antigen-induced immunopathology. J Immunol 1998, 160:5654–5660. This paper presents data that demonstrate a pivotal role for interleukin (IL)-15 in the development of arthritis and suggest that antagonists to IL-15 may have therapeutic potential in rheumatic diseases.

    PubMed  CAS  Google Scholar 

  43. Laan M, Cui ZH, Hoshino H, et al.: Neutrophil recruitment by human IL-17 via C-X-C chemokine release in the airways. J Immunol 1999, 162:2347–2352.

    PubMed  CAS  Google Scholar 

  44. Schwarzenberger P, La Russa V, Miller A, et al.: IL-17 stimulates granulopoiesis in mice: use of an alternate, novel gene therapy-derived method for in vivo evaluation of cytokines. J Immunol 1998, 161:6383–6389.

    PubMed  CAS  Google Scholar 

  45. Chabaud M, Durand JM, Buchs N, et al.: Human interleukin- 17: a T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum 1999, 42:963–970.

    Article  PubMed  CAS  Google Scholar 

  46. 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.

    Article  CAS  Google Scholar 

  47. Lubberts E, Joosten LA,van de Loo FA, et al.: Reduction of interleukin-17-induced inhibition of chondrocyte proteoglycan synthesis in intact murine articular cartilage by interleukin-4. Arthritis Rheum 2000, 43:1300–1306. This paper shows that blocking of endogenous interleukin (IL)-17 in CIA in mice results in suppression of arthritis, including a clear suppression of joint damage. Local overexpression of IL-17 promoted destructive arthritis. Neutralization of IL-1 had no effect on IL-17- induced inflammation and joint damage, identifying an IL-1-independent role for IL-17.

    Article  PubMed  CAS  Google Scholar 

  48. Kong YY, Yoshida H, Sarosi I, et al.: OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymphnode organogenesis. Nature 1999, 397:315–323.

    Article  PubMed  CAS  Google Scholar 

  49. Lubberts E, Joosten LA, Oppers B, et al.: IL-1-independent role of IL-17 in synovial inflammation and joint destruction during collagen-induced arthritis. J Immunol 2001, 167:1004–1013.

    PubMed  CAS  Google Scholar 

  50. Bush KA, Lenarczyk A, Portek I, et al.: Interleukin-17 in rheumatoid arthritis (RA): production by RA synovial membrane cultures and IL-17 receptor (IgG1) fusion protein treatment in rat adjuvant arthritis (AA) [abstract]. Arthritis Rheum 2001, 44:S113.

    Google Scholar 

  51. Chabaud M, Lubberts E, Joosten L,van Den BW, Miossec P: IL- 17 derived from juxta-articular bone and synovium contributes to joint degradation in rheumatoid arthritis. Arthritis Res 2001, 3:168–177.

    Article  PubMed  CAS  Google Scholar 

  52. Chabaud M, Miossec P: The combination of tumor necrosis factor alpha blockade with interleukin-1 and interleukin-17 blockade is more effective for controlling synovial inflammation and bone resorption in an ex vivo model. Arthritis Rheum 2001, 44:1293–1303. The inhibitory effect of sTNFR on IL-6 production and collagen degradation in RA synovium and bone was increased in combination with sIL-17R and sIL-1RII. These results support the concept of combination therapy, which may increase the percentage of responding patients and the degree of the patient response.

    Article  PubMed  CAS  Google Scholar 

  53. Gracie JA, Forsey RJ, Chan WL, et al.: A proinflammatory role for IL-18 in rheumatoid arthritis. J Clin Invest 1999, 104:1393–1401.

    PubMed  CAS  Google Scholar 

  54. Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H: Interleukin- 18 is a unique cytokine that stimulates both Th1 and Th2 responses depending on its cytokine milieu. Cytokine Growth Factor Rev 2001, 12:53–72.

    Article  PubMed  CAS  Google Scholar 

  55. Park CC, Morel JC, Amin MA, et al.: Evidence of IL-18 as a novel angiogenic mediator. J Immunol 2001, 167:1644–1653. A novel function of IL-18 as an angiogenic mediator is reported. This activity can be relevant for the pathogenesis of rheumatoid arthritis.

    PubMed  CAS  Google Scholar 

  56. Leung BP, Culshaw S, Gracie JA, et al.: A role for IL-18 in neutrophil activation. J Immunol 2001, 167:2879–2886.

    PubMed  CAS  Google Scholar 

  57. Olee T, Hashimoto S, Quach J, Lotz M: IL-18 is produced by articular chondrocytes and induces proinflammatory and catabolic responses. J Immunol 1999, 162:1096–1100.

    PubMed  CAS  Google Scholar 

  58. Horwood NJ, Udagawa N, Elliott J, et al.: Interleukin 18 inhibits osteoclast formation via T cell production of granulocyte macrophage colony-stimulating factor. J Clin Invest 1998, 101:595–603.

    PubMed  CAS  Google Scholar 

  59. Leung BP, McInnes IB, Esfandiari E, Wei XQ, Liew FY: Combined effects of IL-12 and IL-18 on the induction of collageninduced arthritis. J Immunol 2000, 164:6495–6502.

    PubMed  CAS  Google Scholar 

  60. Joosten LA,van de Loo FA, Lubberts E, et al.: An IFN-gammaindependent proinflammatory role of IL-18 in murine streptococcal cell wall arthritis. J Immunol 2000, 165:6553–6558.

    PubMed  CAS  Google Scholar 

  61. Wei XQ, Leung BP, Arthur HM, McInnes IB, Liew FY: Reduced incidence and severity of collagen-induced arthritis in mice lacking IL-18. J Immunol 2001, 166:517–521. The results of this paper provide definitive evidence that IL-18 plays a crucial role in the development and sustenance of arthritis.

    PubMed  CAS  Google Scholar 

  62. Plater-Zyberk C, Joosten L, Helsen MM, et al.: IL-18 blockade is a potential disease-modifying therapy for rheumatoid arthritis. Arthritis Res 2001, 3:P092.

    Article  Google Scholar 

  63. Song XY, Gu M, Jin WW, et al.: Plasmid DNA encoding transforming growth factor-beta1 suppresses chronic disease in a streptococcal cell wall-induced arthritis model. J Clin Invest 1998, 101:2615–2621.

    PubMed  CAS  Google Scholar 

  64. Fava R, Olsen N, Keski-Oja J, et al.: Active and latent forms of transforming growth factor beta activity in synovial effusions. J Exp Med 1989, 169:291–296.

    Article  PubMed  CAS  Google Scholar 

  65. van den Berg WB: Joint inflammation and cartilage destruction may occur uncoupled. Springer Semin Immunopathol 1998, 20:149–164.

    Article  PubMed  Google Scholar 

  66. Bakker AC, van de Loo FA,van Beuningen HM, et al.: Overexpression of active TGF-beta-1 in the murine knee joint: evidence for synovial-layer-dependent chondro-osteophyte formation. Osteoarthritis Cartilage 2001, 9:128–136.

    Article  PubMed  CAS  Google Scholar 

  67. Buckley CD, Amft N, Bradfield PF, et al.: Persistent induction of the chemokine receptor CXCR4 by TGF-beta 1 on synovial T cells contributes to their accumulation within the rheumatoid synovium. J Immunol 2000, 165:3423–3429.

    PubMed  CAS  Google Scholar 

  68. Akbar AN, Lord JM, Salmon M: IFN-alpha and IFN-beta: a link between immune memory and chronic inflammation. Immunol Today 2000, 21:337–342.

    Article  PubMed  CAS  Google Scholar 

  69. Triantaphyllopoulos KA, Williams RO, Tailor H, Chernajovsky Y: Amelioration of collagen-induced arthritis and suppression of interferon-gamma, interleukin 12, and tumor necrosis factor alpha production by interferon beta gene therapy. Arthritis Rheum 1999, 42:90–99.

    Article  PubMed  CAS  Google Scholar 

  70. van Holten J, Smeets TJ, Sattonnet-Roche P, et al.: The effects of interferon-beta (IFN-_) treatment on synovial cytokine expression in collagen induced arthritis in DBA/1 mice [abstract]. Arthritis Rheum 2001, 44:S242.

    Article  Google Scholar 

  71. Tak PP, Hart BA, Kraan MC, et al.: The effects of interferon beta treatment on arthritis. Rheumatology (Oxford) 1999, 38:362–369.

    Article  CAS  Google Scholar 

  72. Sundel RP, Wallace CA, Zurakowski D: Pilot trial of interferonbeta- 1a (Avonex) in JRA [abstract]. Arthritis Rheum 2001, 44:S272.

    Google Scholar 

  73. van Roon JAG, Lafeber FP, Bijlsma JW: Synergistic activity of interleukin-4 and interleukin-10 in suppression of inflammation and joint destruction in rheumatoid arthritis. Arthritis Rheum 2001, 44:3–12.

    Article  PubMed  Google Scholar 

  74. Woods JM, Katschke KJJ, Tokuhira M, et al.: Reduction of inflammatory cytokines and prostaglandin E2 by IL-13 gene therapy in rheumatoid arthritis synovium. J Immunol 2000, 165:2755–2763.

    PubMed  CAS  Google Scholar 

  75. Bessis N, Boissier MC, Ferrara P, et al.: Attenuation of collageninduced arthritis in mice by treatment with vector cells engineered to secrete interleukin-13. Eur J Immunol 1996, 26:2399–2403.

    Article  PubMed  CAS  Google Scholar 

  76. Morita Y, Yang J, Gupta R, et al.: Dendritic cells genetically engineered to express IL-4 inhibit murine collagen-induced arthritis. J Clin Invest 2001, 107:1275–1284.

    PubMed  CAS  Google Scholar 

  77. Boyle DL, Nguyen KH, Zhuang S, et al.: Intra-articular IL-4 gene therapy in arthritis: anti-inflammatory effect and enhanced th2 activity. Gene Ther 1999, 6:1911–1918.

    Article  PubMed  CAS  Google Scholar 

  78. Van den Bosch F, Russel A, Keystone EC, et al.: rHuIL-4 in subjects with active rheumatoid arthritis: a phase I dose escalating safety study. Arthritis Rheum 1998, 41:S56.

    Article  Google Scholar 

  79. Maini RN, Paulus H, Breedveld FC, et al.: rHuIL-10 in subjects with active rheumatoid arthritis: a phase I and cytokine response study. Arthritis Rheum 1997, 40:S224.

    Google Scholar 

  80. Hermann JA, Hall MA, Maini RN, et al.: Important immunoregulatory role of interleukin-11 in the inflammatory process in rheumatoid arthritis. Arthritis Rheum 1998, 41:1388–1397.

    Article  PubMed  CAS  Google Scholar 

  81. Walmsley M, Marinova-Mutafchieva L, Butler DM, Feldmann M: An anti-inflammatory role for interleukin-11 in established murine collagen-induced arthritis. Immunology 1998, 94:31–37.

    Article  Google Scholar 

  82. Moreland LW, Gugliotti R, King K, et al.: Results of a phase-I/II randomized, masked, placebo-controlled trial of recombinant human interleukin-11 (rHIL-11) in the treatment of subjects with active rheumatoid arthritis. Arthritis Res 2001, 3:247–252.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vervoordeldonk, M.J.B.M., Tak, P.P. Cytokines in rheumatoid arthritis. Curr Rheumatol Rep 4, 208–217 (2002). https://doi.org/10.1007/s11926-002-0067-0

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11926-002-0067-0

Keywords

Navigation