Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Cytokines in the pathogenesis of rheumatoid arthritis

Key Points

  • Cytokines regulate inflammation, autoimmunity and articular destruction in the joints of patients with rheumatoid arthritis. In particular, tumour-necrosis factor (TNF) has proved to be of particular utility as a therapeutic target.

  • T-cell activation particularly towards a T helper 1 (TH1)-cell and/or a TH17-cell phenotype is associated with the presence in the synovial tissue of interleukin-15 (IL-15), IL-1, IL-6, transforming growth factor-β (TGFβ), IL-12 and IL-23. In turn, T cells drive inflammation via IL-17 release and by cognate interactions with adjacent macrophages.

  • B cells have a critical role in synovitis, acting in part via antigen presentation and cytokine release. B-cell differentiation and expansion, in turn, is supported in the synovial tissue by IL-6, IL-10, B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL).

  • Macrophage-derived cytokines including TNF, IL-1, IL-6, IL-15 and IL-18 drive many of the pro-inflammatory pathways in synovial tissue.

  • Cytokines are responsible for osteoclast maturation and activation. There appears to be a hierarchical role for receptor activator of nuclear factor-κB ligand (RANKL) in this process together with TNF, IL-17 and IL-1.

  • Early intervention, for example with TNF-blocking agents, appears to offer higher clinical response rates and improved chances of achieving clinical remission. Clinical studies are ongoing targeting IL-6, IL-15, IL-18, IL-17, granulocyte/macrophage colony-stimulating factor (GM-CSF) and others, with the objective of further improving clinical outcomes.

Abstract

Cytokines regulate a broad range of inflammatory processes that are implicated in the pathogenesis of rheumatoid arthritis. In rheumatoid joints, it is well known that an imbalance between pro- and anti-inflammatory cytokine activities favours the induction of autoimmunity, chronic inflammation and thereby joint damage. However, it remains less clear how cytokines are organized within a hierarchical regulatory network, and therefore which cytokines may be the best targets for clinical intervention a priori. Here, we discuss the crucial effector function of cytokines in the immunological processes that are central to the pathogenesis of rheumatoid arthritis.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: A contextual framework for the pathogenesis of rheumatoid arthritis.
Figure 2: Pathways leading to activation of synovial T cells in rheumatoid arthritis and their key effector pathways.
Figure 3: An overview of the cytokine-mediated regulation of synovial interactions.
Figure 4: The key factors that regulate osteoclast differentiation in rheumatoid arthritis.
Figure 5: Pathways regulating chondrocyte activation and cartilage degradation in rheumatoid arthritis.

References

  1. 1

    Firestein, G. S. Evolving concepts of rheumatoid arthritis. Nature 423, 356–361 (2003). This is an elegant overview of the pathogenesis of rheumatoid arthritis.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2

    Maini, R. N. & Taylor, P. C. Anti-cytokine therapy for rheumatoid arthritis. Annu. Rev. Med. 51, 207–229 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3

    McInnes, I. B. & Liew, F. Y. Cytokine networks—towards new therapies for rheumatoid arthritis. Nature Clin. Pract. Rheumatol. 1, 31–39 (2005).

    CAS  Article  Google Scholar 

  4. 4

    van der Helm-van Mil, A. H., Wesoly, J. Z. & Huizinga, T. W. Understanding the genetic contribution to rheumatoid arthritis. Curr. Opin. Rheumatol. 17, 299–304 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5

    Klareskog, L., Padyukov, L. & Alfredsson, L. Smoking as a trigger for inflammatory rheumatic diseases. Curr. Opin. Rheumatol. 19, 49–54 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6

    Jimenez-Boj, E. et al. Interaction between synovial inflammatory tissue and bone marrow in rheumatoid arthritis. J. Immunol. 175, 2579–2588 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7

    Nishimoto, N. & Kishimoto, T. Interleukin 6: from bench to bedside. Nature Clin. Pract. Rheumatol. 2, 619–626 (2006).

    CAS  Article  Google Scholar 

  8. 8

    Sattar, N., McCarey, D. W., Capell, H. & McInnes, I. B. Explaining how 'high-grade' systemic inflammation accelerates vascular risk in rheumatoid arthritis. Circulation 108, 2957–2963 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9

    Panayi, G. S. Even though T-cell-directed trials have been of limited success, is there reason for optimism? Nature Clin. Pract. Rheumatol. 2, 58–59 (2006).

    Article  Google Scholar 

  10. 10

    Keystone, E. C. Abandoned therapies and unpublished trials in rheumatoid arthritis. Curr. Opin. Rheumatol. 15, 253–258 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11

    Genovese, M. C. et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor α inhibition. N. Engl. J. Med. 353, 1114–1123 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    McInnes, I. B., Leung, B. P., Sturrock, R. D., Field, M. & Liew, F. Y. Interleukin-15 mediates T cell-dependent regulation of tumor necrosis factor-α production in rheumatoid arthritis. Nature Med. 3, 189–195 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13

    Schulze-Koops, H. & Kalden, J. R. The balance of Th1/Th2 cytokines in rheumatoid arthritis. Best Pract. Res. Clin. Rheumatol. 15, 677–691 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14

    Lubberts, E., Koenders, M. I. & van den Berg, W. B. The role of T-cell interleukin-17 in conducting destructive arthritis: lessons from animal models. Arthritis Res. Ther. 7, 29–37 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15

    Manoury-Schwartz, B. et al. High susceptibility to collagen-induced arthritis in mice lacking IFN-γ receptors. J. Immunol. 158, 5501–5506 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Vermeire, K. et al. Accelerated collagen-induced arthritis in IFN-γ receptor-deficient mice. J. Immunol. 158, 5507–5513 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Murphy, C. A. et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J. Exp. Med. 198, 1951–1957 (2003). This is a critical paper defining the role of T H 17 cells in CIA.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18

    Wang, J. et al. Transcription factor T-bet regulates inflammatory arthritis through its function in dendritic cells. J. Clin. Invest. 116, 414–421 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19

    Alonzi, T. et al. Interleukin 6 is required for the development of collagen-induced arthritis. J. Exp. Med. 187, 461–468 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20

    Hirota, K. et al. T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis. J. Exp. Med. 204, 41–47 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21

    Firestein, G. S. & Zvaifler, N. J. Peripheral blood and synovial fluid monocyte activation in inflammatory arthritis. II. Low levels of synovial fluid and synovial tissue interferon suggest that γ-interferon is not the primary macrophage activating factor. Arthritis Rheum. 30, 864–871 (1987).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22

    Kanik, K. S. et al. Distinct patterns of cytokine secretion characterize new onset synovitis versus chronic rheumatoid arthritis. J. Rheumatol. 25, 16–22 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Ronnelid, J. et al. Production of T-cell cytokines at the single-cell level in patients with inflammatory arthritides: enhanced activity in synovial fluid compared to blood. Br. J. Rheumatol. 37, 7–14 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24

    Chabaud, M. et al. Human interleukin-17: a T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum. 42, 963–970 (1999). This paper reports the first description of IL-17 in the rheumatoid arthritis synovium.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25

    Goldberg, R., Wildbaum, G., Zohar, Y., Maor, G. & Karin, N. Suppression of ongoing adjuvant-induced arthritis by neutralizing the function of the p28 subunit of IL-27. J. Immunol. 173, 1171–1178 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26

    Batten, M. et al. Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nature Immunol. 7, 929–936 (2006).

    CAS  Article  Google Scholar 

  27. 27

    Stumhofer, J. S. et al. Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nature Immunol. 7, 937–945 (2006).

    CAS  Article  Google Scholar 

  28. 28

    Weaver, C. T., Hatton, R. D., Mangan, P. R. & Harrington, L. E. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu. Rev. Immunol. 25, 821–852 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29

    Raza, K. et al. Early rheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin. Arthritis Res. Ther. 7, R784–R795 (2005). This is an important paper defining the early cytokine expression profile in synovial fluid.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30

    Skapenko, A., Leipe, J., Lipsky, P. E. & Schulze-Koops, H. The role of the T cell in autoimmune inflammation. Arthritis. Res. Ther. 7 (Suppl. 2), 4–14 (2005).

    Article  Google Scholar 

  31. 31

    Ehrenstein, M. R. et al. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFα therapy. J. Exp. Med. 200, 277–285 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32

    Nadkarni, S., Mauri, C. & Ehrenstein, M. R. Anti-TNF-α therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-β. J. Exp. Med. 204, 33–39 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33

    Weyand, C. M. & Goronzy, J. J. T-cell-targeted therapies in rheumatoid arthritis. Nature Clin. Pract. Rheumatol. 2, 201–210 (2006).

    CAS  Article  Google Scholar 

  34. 34

    Schroder, A. E., Greiner, A., Seyfert, C. & Berek, C. Differentiation of B cells in the nonlymphoid tissue of the synovial membrane of patients with rheumatoid arthritis. Proc. Natl. Acad. Sci. USA 93, 221–225 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35

    Isomaki, P. et al. Prolonged exposure of T cells to TNF down-regulates TCRζ and expression of the TCR/CD3 complex at the cell surface. J. Immunol. 166, 5495–5507 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36

    Veys, E. M., Menkes, C. J. & Emery, P. A randomized, double-blind study comparing twenty-four-week treatment with recombinant interferon-γ versus placebo in the treatment of rheumatoid arthritis. Arthritis Rheum. 40, 62–68 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37

    Miossec, P. Interleukin-17 in rheumatoid arthritis: if T cells were to contribute to inflammation and destruction through synergy. Arthritis Rheum. 48, 594–601 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38

    Steinman, L. A brief history of TH17, the first major revision in the TH1/TH2 hypothesis of T cell-mediated tissue damage. Nature Med. 13, 139–145 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39

    Zheng, Y. et al. Interleukin-22, a TH17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 445, 648–651 (2007).

    CAS  Article  PubMed  Google Scholar 

  40. 40

    Ikeuchi, H. et al. Expression of interleukin-22 in rheumatoid arthritis: potential role as a proinflammatory cytokine. Arthritis Rheum. 52, 1037–1046 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41

    Yumoto, K. et al. Osteopontin deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in mice. Proc. Natl. Acad. Sci. USA 99, 4556–4561 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Xu, G. et al. Role of osteopontin in amplification and perpetuation of rheumatoid synovitis. J. Clin. Invest. 115, 1060–1067 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43

    Brennan, F. M. et al. Evidence that rheumatoid arthritis synovial T cells are similar to cytokine-activated T cells: involvement of phosphatidylinositol 3-kinase and nuclear factor κB pathways in tumor necrosis factor α production in rheumatoid arthritis. Arthritis Rheum. 46, 31–41 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    Dayer, J. M. & Burger, D. Cell–cell interactions and tissue damage in rheumatoid arthritis. Autoimmun. Rev. 3 (Suppl. 1), 14–16 (2004).

    Google Scholar 

  45. 45

    McInnes, I. B., Leung, B. P. & Liew, F. Y. Cell–cell interactions in synovitis. Interactions between T lymphocytes and synovial cells. Arthritis Res. 2, 374–378 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46

    Edwards, J. C. et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N. Engl. J. Med. 350, 2572–2581 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47

    Takemura, S., Klimiuk, P. A., Braun, A., Goronzy, J. J. & Weyand, C. M. T cell activation in rheumatoid synovium is B cell dependent. J. Immunol. 167, 4710–4718 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. 48

    Seyler, T. M. et al. BLyS and APRIL in rheumatoid arthritis. J. Clin. Invest. 115, 3083–3092 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49

    Ohata, J. et al. Fibroblast-like synoviocytes of mesenchymal origin express functional B cell-activating factor of the TNF family in response to proinflammatory cytokines. J. Immunol. 174, 864–870 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50

    Dorner, T. & Lipsky, P. E. Signalling pathways in B cells: implications for autoimmunity. Curr. Top. Microbiol. Immunol. 305, 213–240 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Takemura, S. et al. Lymphoid neogenesis in rheumatoid synovitis. J. Immunol. 167, 1072–1080 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52

    Manzo, A. et al. Systematic microanatomical analysis of CXCL13 and CCL21 in situ production and progressive lymphoid organization in rheumatoid synovitis. Eur. J. Immunol. 35, 1347–1359 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53

    Weyand, C. M. & Goronzy, J. J. Ectopic germinal center formation in rheumatoid synovitis. Ann. NY Acad. Sci. 987, 140–149 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54

    Braun, A., Takemura, S., Vallejo, A. N., Goronzy, J. J. & Weyand, C. M. Lymphotoxin b-mediated stimulation of synoviocytes in rheumatoid arthritis. Arthritis Rheum. 50, 2140–2150 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. 55

    Lindhout, E. et al. Fibroblast-like synoviocytes from rheumatoid arthritis patients have intrinsic properties of follicular dendritic cells. J. Immunol. 162, 5949–5956 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Kang, Y. M. et al. CD8 T cells are required for the formation of ectopic germinal centers in rheumatoid synovitis. J. Exp. Med. 195, 1325–1336 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57

    Brentano, F., Kyburz, D., Schorr, O., Gay, R. & Gay, S. The role of Toll-like receptor signalling in the pathogenesis of arthritis. Cell Immunol. 233, 90–96 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58

    Seibl, R. et al. Expression and regulation of Toll-like receptor 2 in rheumatoid arthritis synovium. Am. J. Pathol. 162, 1221–1227 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59

    Joosten, L. A. et al. Toll-like receptor 2 pathway drives streptococcal cell wall-induced joint inflammation: critical role of myeloid differentiation factor 88. J. Immunol. 171, 6145–6153 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60

    Sacre, S. M. et al. The Toll-like receptor adaptor proteins MyD88 and Mal/TIRAP contribute to the inflammatory and destructive processes in a human model of rheumatoid arthritis. Am. J. Pathol. 170, 518–525 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61

    Kelso, E. B. et al. Therapeutic promise of proteinase-activated receptor-2 antagonism in joint inflammation. J. Pharmacol. Exp. Ther. 316, 1017–1024 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62

    Kelso, E. B. et al. Expression and proinflammatory role of proteinase-activated receptor 2 in rheumatoid synovium: ex vivo studies using a novel proteinase-activated receptor 2 antagonist. Arthritis Rheum. 56, 765–771 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. 63

    Feldmann, M., Brennan, F. M. & Maini, R. N. Rheumatoid arthritis. Cell 85, 307–310 (1996). This is a seminal review of the balance of cytokine activities in rheumatoid arthritis.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. 64

    Feldmann, M., Brennan, F. M. & Maini, R. N. Role of cytokines in rheumatoid arthritis. Annu. Rev. Immunol. 14, 397–440 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. 65

    Keffer, J. et al. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J. 10, 4025–4031 (1991).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 66

    Quinn, M. A. et al. Very early treatment with infliximab in addition to methotrexate in early, poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained benefit after infliximab withdrawal: results from a twelve-month randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 52, 27–35 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. 67

    Ferrari-Lacraz, S. et al. Targeting IL-15 receptor-bearing cells with an antagonist mutant IL-15/Fc protein prevents disease development and progression in murine collagen-induced arthritis. J. Immunol. 173, 5818–5826 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 68

    Baslund, B. et al. Targeting interleukin-15 in patients with rheumatoid arthritis: a proof-of-concept study. Arthritis Rheum. 52, 2686–2692 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. 69

    Dayer, J. M. & Bresnihan, B. Targeting interleukin-1 in the treatment of rheumatoid arthritis. Arthritis Rheum. 46, 574–578 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. 70

    Horai, R. et al. Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice. J. Exp. Med. 191, 313–320 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. 71

    Hoffman, H. M. et al. Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet 364, 1779–1785 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. 72

    Choe, J. Y., Crain, B., Wu, S. R. & Corr, M. Interleukin 1 receptor dependence of serum transferred arthritis can be circumvented by Toll-like receptor 4 signaling. J. Exp. Med. 197, 537–542 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73

    Gracie, J. A. et al. A proinflammatory role for IL-18 in rheumatoid arthritis. J. Clin. Invest. 104, 1393–1401 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  74. 74

    McInnes, I. B., Liew, F. Y. & Gracie, J. A. Interleukin-18: a therapeutic target in rheumatoid arthritis? Arthritis Res. Ther. 7, 38–41 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. 75

    Joosten, L. A. et al. IL-32, a proinflammatory cytokine in rheumatoid arthritis. Proc. Natl Acad. Sci. USA 103, 3298–3303 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. 76

    Netea, M. G. et al. IL-32 synergizes with nucleotide oligomerization domain (NOD) 1 and NOD2 ligands for IL-1β and IL-6 production through a caspase 1-dependent mechanism. Proc. Natl Acad. Sci. USA 102, 16309–16314 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77

    Kokkola, R. et al. High mobility group box chromosomal protein 1: a novel proinflammatory mediator in synovitis. Arthritis Rheum. 46, 2598–2603 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. 78

    Morand, E. F., Leech, M. & Bernhagen, J. MIF: a new cytokine link between rheumatoid arthritis and atherosclerosis. Nature Rev. Drug Discov. 5, 399–410 (2006).

    CAS  Article  Google Scholar 

  79. 79

    van der Pouw Kraan, T. C. et al. Rheumatoid arthritis subtypes identified by genomic profiling of peripheral blood cells: assignment of a type I interferon signature in a subpopulation of patients. Ann. Rheum. Dis. 18 January 2007 (doi:10.1136/ard.2006.063412).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. 80

    Edwards, S. W. & Hallett, M. B. Seeing the wood for the trees: the forgotten role of neutrophils in rheumatoid arthritis. Immunol. Today 18, 320–324 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. 81

    Woolley, D. E. The mast cell in inflammatory arthritis. N. Engl. J. Med 348, 1709–1711 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. 82

    Lee, D. M. et al. Mast cells: a cellular link between autoantibodies and inflammatory arthritis. Science 297, 1689–1692 (2002).

    CAS  Article  Google Scholar 

  83. 83

    Paniagua, R. T. et al. Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis. J. Clin. Invest. 116, 2633–2642 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. 84

    Dalbeth, N. & Callan, M. F. A subset of natural killer cells is greatly expanded within inflamed joints. Arthritis Rheum. 46, 1763–1772 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  85. 85

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. 86

    Schett, G. et al. High-sensitivity C-reactive protein and risk of nontraumatic fractures in the Bruneck study. Arch. Intern. Med. 166, 2495–2501 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  87. 87

    Pasco, J. A. et al. High-sensitivity C-reactive protein and fracture risk in elderly women. JAMA 296, 1353–1355 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. 88

    Goldring, S. R. Inflammatory mediators as essential elements in bone remodeling. Calcif. Tissue Int. 73, 97–100 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. 89

    Teitelbaum, S. L. Bone resorption by osteoclasts. Science 289, 1504–1508 (2000).

    CAS  Article  PubMed  Google Scholar 

  90. 90

    Redlich, K. et al. Osteoclasts are essential for TNF-α-mediated joint destruction. J. Clin. Invest. 110, 1419–1427 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  91. 91

    Gravallese, E. M. et al. Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum. 43, 250–258 (2000). This paper reports the important early description of the erosive potential in inflammatory synovitis.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  92. 92

    Yoshida, H. et al. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 345, 442–444 (1990).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  93. 93

    Seitz, M., Loetscher, P., Fey, M. F. & Tobler, A. Constitutive mRNA and protein production of macrophage colony-stimulating factor but not of other cytokines by synovial fibroblasts from rheumatoid arthritis and osteoarthritis patients. Br. J. Rheumatol. 33, 613–619 (1994).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. 94

    Lacey, D. L. et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93, 165–176 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  95. 95

    Kong, Y. Y. et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402, 304–309 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  96. 96

    Shigeyama, Y. et al. Expression of osteoclast differentiation factor in rheumatoid arthritis. Arthritis Rheum. 43, 2523–2530 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. 97

    Horwood, N. J., Elliott, J., Martin, T. J. & Gillespie, M. T. Osteotropic agents regulate the expression of osteoclast differentiation factor and osteoprotegerin in osteoblastic stromal cells. Endocrinology 139, 4743–4746 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  98. 98

    Kotake, S. et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J. Clin. Invest. 103, 1345–1352 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  99. 99

    Simonet, W. S. et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89, 309–319 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  100. 100

    Lam, J. et al. TNF-α induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J. Clin. Invest. 106, 1481–1488 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  101. 101

    Li, P. et al. RANK signaling is not required for TNFα-mediated increase in CD11hi osteoclast precursors but is essential for mature osteoclast formation in TNFα-mediated inflammatory arthritis. J. Bone. Miner. Res. 19, 207–213 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  102. 102

    Ritchlin, C. T., Haas-Smith, S. A., Li, P., Hicks, D. G. & Schwarz, E. M. Mechanisms of TNF-α- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis. J. Clin. Invest. 111, 821–831 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  103. 103

    Wei, S., Kitaura, H., Zhou, P., Ross, F. P. & Teitelbaum, S. L. IL-1 mediates TNF-induced osteoclastogenesis. J. Clin. Invest. 115, 282–290 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  104. 104

    Wong, P. K. et al. Interleukin-6 modulates production of T lymphocyte-derived cytokines in antigen-induced arthritis and drives inflammation-induced osteoclastogenesis. Arthritis Rheum. 54, 158–168 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. 105

    Sato, K. et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J. Exp. Med. 203, 2673–2682 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  106. 106

    Takayanagi, H. et al. T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ. Nature 408, 600–605 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  107. 107

    Udagawa, N. et al. Interleukin-18 (interferon-γ-inducing factor) is produced by osteoblasts and acts via granulocyte/macrophage colony-stimulating factor and not via interferon-γ to inhibit osteoclast formation. J. Exp. Med. 185, 1005–1012 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  108. 108

    Bertolini, D. R., Nedwin, G. E., Bringman, T. S., Smith, D. D. & Mundy, G. R. Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors. Nature 319, 516–518 (1986).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  109. 109

    Diarra, D. et al. Dickkopf-1 is a master regulator of joint remodeling. Nature Med. 13, 156–163 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  110. 110

    Meyer, L. H., Franssen, L. & Pap, T. The role of mesenchymal cells in the pathophysiology of inflammatory arthritis. Best Pract. Res. Clin. Rheumatol. 20, 969–981 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  111. 111

    Lee, D. M. et al. Cadherin-11 in synovial lining formation and pathology in arthritis. Science 315, 1006–1010 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  112. 112

    Pap, T., Muller-Ladner, U., Gay, R. E. & Gay, S. Fibroblast biology: role of synovial fibroblasts in the pathogenesis of rheumatoid arthritis. Arthritis Res. 2, 361–367 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  113. 113

    Burger, J. A., Zvaifler, N. J., Tsukada, N., Firestein, G. S. & Kipps, T. J. Fibroblast-like synoviocytes support B-cell pseudoemperipolesis via a stromal cell-derived factor-1- and CD106 (VCAM-1)-dependent mechanism. J. Clin. Invest. 107, 305–315 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  114. 114

    Pap, T. Direct interaction of immunoglobulins with synovial fibroblasts: a missing link in the pathogenesis of rheumatoid arthritis? Arthritis Res. Ther. 7, 44–46 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  115. 115

    Eberhardt, W., Huwiler, A., Beck, K. F., Walpen, S. & Pfeilschifter, J. Amplification of IL-1β-induced matrix metalloproteinase-9 expression by superoxide in rat glomerular mesangial cells is mediated by increased activities of NF-κB and activating protein-1 and involves activation of the mitogen-activated protein kinase pathways. J. Immunol. 165, 5788–5797 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  116. 116

    Catterall, J. B. et al. Synergistic induction of matrix metalloproteinase 1 by interleukin-1α and oncostatin M in human chondrocytes involves signal transducer and activator of transcription and activator protein 1 transcription factors via a novel mechanism. Arthritis Rheum. 44, 2296–2310 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  117. 117

    Van den Berg, W. B. Lessons from animal models of arthritis. Curr. Rheumatol. Rep. 4, 232–239 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  118. 118

    Pettipher, E. R., Higgs, G. A. & Henderson, B. Interleukin 1 induces leukocyte infiltration and cartilage proteoglycan degradation in the synovial joint. Proc. Natl Acad. Sci. USA 83, 8749–8753 (1986).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  119. 119

    Joosten, L. A. B. et al. Interleukin-18 Promotes joint inflammation and induces interleukin-1-driven cartilage destruction. Am. J. Pathol. 165, 959–967 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  120. 120

    Dudler, J., Renggli-Zulliger, N., Busso, N., Lotz, M. & So, A. Effect of interleukin 17 on proteoglycan degradation in murine knee joints. Ann. Rheum. Dis. 59, 529–532 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  121. 121

    Lubberts, E. et al. Overexpression of IL-17 in the knee joint of collagen type II immunized mice promotes collagen arthritis and aggravates joint destruction. Inflamm. Res. 51, 102–104 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  122. 122

    Cai, L. et al. Pathways by which interleukin 17 induces articular cartilage breakdown in vitro and in vivo. Cytokine 16, 10–21 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  123. 123

    Veale, D. J. & Fearon, U. Inhibition of angiogenic pathways in rheumatoid arthritis: potential for therapeutic targeting. Best Pract. Res. Clin. Rheumatol. 20, 941–947 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  124. 124

    Paleolog, E. M. Angiogenesis in rheumatoid arthritis. Arthritis Res. 4 (Suppl. 3), 81–90 (2002).

    Article  Google Scholar 

  125. 125

    Loetscher, P. et al. CCR5 is characteristic of Th1 lymphocytes. Nature 391, 344–345 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  126. 126

    Haringman, J. J. & Tak, P. P. Chemokine blockade: a new era in the treatment of rheumatoid arthritis? Arthritis Res. Ther. 6, 93–97 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  127. 127

    Koch, A. E. Chemokines and their receptors in rheumatoid arthritis: future targets? Arthritis Rheum. 52, 710–721 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  128. 128

    Goekoop-Ruiterman, Y. P. et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum. 52, 3381–3390 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  129. 129

    McInnes, I. B. Cytokines. In Kelley's Textbook of Rheumatology. 7th edn. (eds Harris, E. D. Jr. et al.) Ch. 15 (Elsevier Saunders, Philadelphia (2005).

    Google Scholar 

Download references

Acknowledgements

We are grateful for financing from the Arthritis Research Campaign (UK) and The Wellcome Trust. We thank J. A. Gracie for invaluable contribution to the preparation and content of this manuscript. We are grateful for discussions with many colleagues concerning ideas contained within the content, particularly F. Y. Liew, G. Graham, P. Garside and G. Firestein. We apologize to colleagues whose work is cited via review rather than original work owing to space restraints.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Iain B. McInnes.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Glossary

Citrullinated peptide

A peptide that incorporates the amino-acid citrulline. This amino acid is generated post-translationally by peptidylarginine deiminases. Patients with rheumatoid arthritis generate characteristic autoantibodies against the part of the antigenic determinant that contains citrulline moieties.

Shared epitope

A common stretch of amino acids in the peptide-binding grooves at positions 67–74 of the HLA-DRβ-chain.

Osteoclasts

Multinucleated giant cells, of the monocyte lineage, that are responsible for bone resorption. Osteoclasts degrade bone matrix and solubilize calcium from bone. Problems with their differentiation and a decrease in their number lead to bone osteopetrosis. Conversely, an increase in their number or function induces bone osteoporosis, indicating that osteoclasts have a pivotal role in bone homeostasis.

Acute-phase proteins

A group of proteins, including C-reactive protein, serum amyloid A, fibrinogen and α1-acid glycoprotein, that are secreted into the blood in increased or decreased quantities by hepatocytes in response to trauma, inflammation or disease. These proteins can be inhibitors or mediators of inflammatory processes.

Cachexia

Severe weight loss, muscle wasting and debility caused by prolonged disease. It is thought to be mediated through neuroimmunoendocrine interactions.

Cyclosporin

A commonly used immunosuppressive drug that blocks calcineurin A and thereby inhibits T-cell activation. It is used to prevent the rejection of transplanted organs and to treat some inflammatory diseases.

Collagen-induced arthritis

(CIA). An animal model of rheumatoid arthritis. CIA develops in susceptible rodents and primates after immunization with cartilage-derived type II collagen.

T-bet

A member of the T-box family of transcription factors. It is a master switch in the development of T helper 1 (TH1)-cell responses, through its ability to regulate expression of the interleukin-12 receptor, inhibit signals that promote TH2-cell development and promote the production of interferon-γ.

ELISPOT

A method based on antibody capture for enumerating specific T cells (CD4+ and CD8+) that secrete a particular cytokine (often interferon-γ).

Plasmacytoid DC

A dendritic cell (DC) subset with a morphology that resembles that of a plasmablast. Plasmacytoid DCs produce large amounts of type I interferons in response to viral infection.

Adjuvant-induced arthritis

An experimental animal model of arthritis, in which disease is induced by the administration of heat-killed mycobacteria in oil.

Follicular DCs

These are specialized non-haematopoietic stromal cells that reside in the follicles and germinal centres. These cells possess long dendrites, but are not related to dendritic cells, and carry intact antigen on their surface.

Germinal centres

Highly specialized and dynamic microenvironments that give rise to secondary B-cell follicles during an immune response. They are the main site of B-cell maturation, leading to the generation of memory B cells and plasma cells that produce high-affinity antibody.

SCID mouse

Severe combined immunodeficiency mouse. Mice of this phenotype lack functional T and B cells owing to a spontaneous mutation in the Prkdc gene (protein kinase, DNA activated, catalytic polypeptide) located on chromosome 16. These mice are often used for reconstitution of T-cell subsets to study their functions in vivo.

Affinity maturation

A process whereby the mutation of antibody variable (V)-region genes followed by selection for higher-affinity variants in the germinal centre leads to an increase in average antibody affinity for an antigen as an immune response progresses. The selection is thought to be a competitive process in which B cells compete with free antibody to capture decreasing amounts of antigen.

Receptor editing

A molecular process that involves secondary rearrangements (mostly of the light chains) that replace existing immunoglobulin molecules and generate a new antigen receptor with altered specificity.

Mantle zone

The area of a secondary follicle that surrounds the germinal centre and contains IgD+ naive, resting B cells.

Danger signals

Agents that alert the immune system to danger, usually by interacting with Toll-like receptors and other pattern-recognition receptors, and thereby promote the generation of innate and adaptive immune responses. Danger signals can be associated with microbial invaders (exogenous danger signals) or produced by damaged cells (endogenous danger signals).

IL-1 receptor antagonist

(IL-1RA). A secreted protein that binds to the interleukin-1 receptor (IL-1R), thereby blocking IL-1R downstream signalling. IL-1RA inhibits the pro-inflammatory properties of IL-1α and IL-1β.

K/BxN transgenic mouse

A mouse strain formed by crossing NOD/Lt mice with C57BL/6 KRN T-cell-receptor-transgenic mice in which T cells recognize a peptide from the autoantigen glucose-6-phosphate isomerase (GPI). These mice develop an arthritis that is mediated, and transferable, by circulating antibody against GPI.

Pannus

A sheet of inflammatory granulation tissue, composed of immune cells, blood vessels and fibrous cells, that spreads from the synovial membrane and ultimately invades the joint in rheumatoid arthritis.

Osteoblasts

Cells of mesenchymal origin that are responsible for the formation of bone.

Diapedesis

The migration of leukocytes across the endothelium, which occurs by leukocytes squeezing through the junctions between adjacent endothelial cells.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

McInnes, I., Schett, G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol 7, 429–442 (2007). https://doi.org/10.1038/nri2094

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing