Role of IL-1 in erosive arthritis, lessons from animal models

  • Wim B. van den Berg
  • Leo A. B. Joosten
  • Fons A. J. van de Loo
Part of the Progress in Inflammation Research book series (PIR)


Tumor necrosis factor (TNF), interleukin-1 (IL-1) and IL-6 are considered master cytokines in chronic destructive arthritis. IL-1 drives chronic erosive arthritis and its blockade has been shown to ameliorate joint destruction in many animal models of arthritis. This ranges from a dominant role of IL-1 in immune complex arthritis, to a key role in development of T cell-dependent arthritis and TNF transgenic arthritis. This makes IL-1 an attractive therapeutic target, in addition to TNF and IL-6. However, IL-1 dependency can be lost under conditions of T cell IL-17 abundance as well as the presence of Toll-like receptor ligands. The latter may underlie the variable responsiveness of rheumatoid arthritis patients to anti-cytokine therapy and warrants combination therapy for optimal control.


P2X7 Receptor Autoimmune Arthritis Erosive Arthritis Streptococcal Cell Wall Destructive Arthritis 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    van Lent PL, Grevers L, Lubberts E, de Vries TJ, Nabbe KC, Verbeek S, Oppers B, Sloetjes A, Blom AB, van den Berg WB (2006) FcgammaRs directly mediate cartilage but not bone destruction in murine antigen induced arthritis: Uncoupling of cartilage damage from bone erosion and joint inflammation. Arthritis Rheum 54: 3868–77PubMedCrossRefGoogle Scholar
  2. 2.
    Schaefer L, Babelova A, Kiss E, Hausse HJ, Baliova M, Kryzankova M, Marsche G, Young MF, Mihalik D, Gotte M et al (2005) The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages. J Clin Invest 115: 2223–2233PubMedCrossRefGoogle Scholar
  3. 3.
    Arend WP, Dayer JM (1995) Inhibition of the production and effects of IL-1 and TNFα in RA. Arthritis Rheum 38: 151–160PubMedCrossRefGoogle Scholar
  4. 4.
    Sims JE, Nicklin MJ, Bazan JF, Barton JL, Busfield SJ, Ford JE, Kastelein RA, Kumar S, Lin H, Mulero JJ et al (2001) A new nomenclature for IL-1-family genes. Trends Immunol 22: 536–537PubMedCrossRefGoogle Scholar
  5. 5.
    Burger D, Dayer JM, Palmer G, Gabay C (2006) Is IL-1 a good therapeutic target in the treatment of arthritis? Best Pract Res Clin Rheumatol 20: 879–96PubMedCrossRefGoogle Scholar
  6. 6.
    Dinarello CA (2005) Blocking IL-1 in systemic inflammation. J Exp Med 201: 1355–1359PubMedCrossRefGoogle Scholar
  7. 7.
    Tschopp J, Martinon F, Burns K et al (2003) NALPs: A novel protein family involved in inflammation. Nat Rev Mol Cell Biol 4: 95–104PubMedCrossRefGoogle Scholar
  8. 8.
    Elssner A, Duncan M, Gavrilin M, Wevers MD (2004) A novel P2X7 receptor activator, the human cathelicidin-derived peptide LL37, induces IL-1 beta processing and release. J Immunol 172: 4987–4994PubMedGoogle Scholar
  9. 9.
    Coeshott C, Ohnemus C, Pilyavskaya A, Ross S, Wieczorek M, Kroona H, Leimer AH, Chernis J (1999) Converting enzyme-independent release of TNFα and IL-1β from a stimulated human monocytic cell line in the presence of activated neutrophils or purified proteinase 3. Proc Natl Acad Sci USA 96: 6261–6266PubMedCrossRefGoogle Scholar
  10. 10.
    Janssens S, Beyaert R (2003) Functional diversity and regulation of different interleukin-1 receptor associated kinases (IRAK) family members. Mol Cell 11: 293–302PubMedCrossRefGoogle Scholar
  11. 11.
    Smeets RL, Joosten LA, Arntz OJ, Bennink MB, Takahashi N, Carlsen H, Martin MU, van den Berg WB, van de Loo FA (2005) Soluble IL-1RacP ameliorates collagen induced arthritis by a different mode of action from that of IL-1ra. Arthritis Rheum 52: 2202–11PubMedCrossRefGoogle Scholar
  12. 12.
    Bresnihan B, Newmark R, Robbins S, Genant HK (2004) Effects of Anakinra monotherapy on joint damage in patients with RA. Extension of a 24-week randomized, placebo-controlled trial. J Rheumatol 31: 1103–11PubMedGoogle Scholar
  13. 13.
    Van de Loo A.A.J. van den Berg WB (1990) Effects of murine recombinant IL-1 on synovial joint in mice: Measurement of patellar cartilage metabolism and joint inflammation. Ann Rheum Dis 49: 238–245PubMedCrossRefGoogle Scholar
  14. 14.
    Niki Y, Yamada H, Seki S, Kikuchi T, Takaishi H, Toyama Y, Fujikawa K, Tada N (2001) Macrophage and neutrophil dominant arthritis in human IL-1 alpha transgenic mice J Clin Invest 107: 1127–35PubMedCrossRefGoogle Scholar
  15. 15.
    Niki Y, Yamada H, Kikuchi T, Toyama Y, Matsumoto H, Fujikawa K, Tada N (2004) Membrane-associated IL-1 contributes to chronic synovitis and cartilage destruction in human IL-1alpha transgenic mice. J Immunol 172: 577–84PubMedGoogle Scholar
  16. 16.
    Probert L, Plows D, Kontogerogos G, Kollias G (1995) The type I IL-1 receptor acts in series with TNFα to induce arthritis in TNFα transgenic mice. Eur J Immunol 25: 1794–97PubMedCrossRefGoogle Scholar
  17. 17.
    Zwerina J, Redlich K, Polzer K, Joosten LA, Kroenke G, Distler J, Hess A, Pundt N, Pap T, Hoffman O et al (2007) TNF-induced structural joint damage is mediated by IL-1. Proc Natl Acad Sci USA 104: 11742–47PubMedCrossRefGoogle Scholar
  18. 18.
    Wei S, Kitaura H, Zhou P, Ross FP, Teitelbaum SL (2005) IL-1 mediates TNF-induced osteoclastogenesis. J Clin Invest 115: 282–290PubMedGoogle Scholar
  19. 19.
    Joosten LA, Helsen MA, van de Loo FA, van den Berg WB (1996) Anticytokine treatment of established type II collagen-induced arthritis in DBA/1 mice. A comparative study using anti-TNF alpha, anti-IL-1 alpha/beta, and IL-1Ra. Arthritis Rheum 39: 797–809PubMedCrossRefGoogle Scholar
  20. 20.
    Mori L, Iselin S, Delibero G, Lesslauer W (1996) Attenuation of collagen-induced arthritis in 55-kD TNF receptor type I (TNFR1)-IgG1 treated and TNFR1-deficient mice. J Immunol 157: 3178–3182PubMedGoogle Scholar
  21. 21.
    Campbell IK, O’Donnel K, Lawlor KE, Wicks IP (2001) Severe inflammatory arthritis and lymphadenopathy on the absence of TNF. J Clin Invest 107: 1519–1527PubMedCrossRefGoogle Scholar
  22. 22.
    Alten RH, Pohl CC, Batard YY, Wright AA, Gram HH, Bobadilla MM (2006) ACR 20/50/70 responses in MTX resistant RA patients in a double blind, placebo controlled phase 1/II evaluation of the pharmacokinetics / pharmacodynamics, safety, and preliminary efficacy of a fully human anti-IL-1β monoclonal antibody ACZ8985. Ann Rheum Dis 65 (Suppl II): 60Google Scholar
  23. 23.
    Ma YS, Thornton GP, Boivin D, Hirsch R, Hirsch E (1998) Altered susceptibility to collagen induced arthritis in transgenic mice with aberrant expression of IL-1ra. Arthritis Rheum 41: 1798–1805PubMedCrossRefGoogle Scholar
  24. 24.
    Lubberts E, Koenders MI, van den Berg WB (2005) The role of IL-17 in conducting destructive arthritis: Lessons from animal models. Arthritis Res Ther 7: 29–37PubMedCrossRefGoogle Scholar
  25. 25.
    van de Loo FAJ, Joosten LAB, van Lent PL, Arntz OJ, van den Berg WB (1995) Role of IL-1, TNF and IL-6 in cartilage proteoglycan metabolism and destruction: Effect of in situ cytokine blocking in murine antigen and zymosan induced arthritis. Arthritis Rheum 38: 164–72PubMedCrossRefGoogle Scholar
  26. 26.
    van Meurs JBJ, van Lent PL, Singer II, Bayne EK, van de Loo FAJ, van den Berg WB (1998) IL-1ra prevents expression of the metalloproteinase generated neoepitope VDIPEN in antigen induced arthritis. Arthritis Rheum 41: 647–56PubMedCrossRefGoogle Scholar
  27. 27.
    Koenders MI, Lubberst E, Oppers-Walgreen B, van den Bersselaar L, Helsen MMA, DiPadova FE, Boots AM, Gram H, Joosten LA, van den Berg WB (2005) Blocking of IL-17 during reactivation of experimental arthritis prevents joint inflammation and bone erosion by decreasing RANKL and IL-1. Am J Pathol 167: 141–49PubMedGoogle Scholar
  28. 28.
    van Lent PL, van de Loo FA, Holthuysen AE, van den Bersselaar LA, Vermeer H, van den Berg WB (1995) Major role for IL-1 but not for TNF in early cartilage damage in immune complex arthritis in mice. J Rheumatol 22: 2250–58PubMedGoogle Scholar
  29. 29.
    Monach PI, Benoist C, Mathis D (2004) The role of antibodies in mouse models of RA and relevance to human disease. Adv Immunol 82: 217–48PubMedCrossRefGoogle Scholar
  30. 30.
    Nigrovic PA, Binstadt BA, Monach PA, Johnson A, Gurish M, Iwakura Y, Benoist C, Mathis D, Lee DM (2007) Mast cells contribute to initiation of autoantibody-mediated arthritis via IL-1. Proc Natl Acad Sci USA 104: 2325–30PubMedCrossRefGoogle Scholar
  31. 31.
    Bendele AM, Chipala ES, Scherrer J, Frazier J, Sennelo G, Rich WJ, Edwards CK III (2000) Combination benefit of treatment with the cytokine inhibitors IL-1ra and PEGylated soluble TNF receptor type I in animals of rheumatoid arthritis. Arthritis Rheum 43: 2648–59PubMedCrossRefGoogle Scholar
  32. 32.
    Horai R, Saijo S, Tanioka H, Nakae S, Sudo K, Okahara A, Ikuse T, Asano M, Iwakura Y (2000) Development of chronic inflammatory arthropathy resembling RA in IL-1ra deficient mice. J Exp Med 191: 313–20PubMedCrossRefGoogle Scholar
  33. 33.
    Horai R, Nakajima A, Habiro K, Kotani M, Nakae S, Matsuki T, Nambu A, Saijo S, Kotaki H, Sudo K et al (2004) TNFα is crucial for the development of autoimmune arthritis in IL-1ra deficient mice. J Clin Invest 114: 1603–11PubMedGoogle Scholar
  34. 34.
    Nakae S, Saiijo S, Horai R, Sudo K, Mori S, Iwakura Y (2003) Il-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1ra. Proc Natl Acad Sci USA 100: 5986–90PubMedCrossRefGoogle Scholar
  35. 35.
    Hata H, Sakaguchi N, Yoshitomi H, Iwakura Y, Sekikawa K, Azuma Y, Kanai C, Moriizumi E, Nomura T, Nakamura T et al (2004) Distinct contribution of IL-6, TNFα, IL-1 and IL-10 to T cell mediated spontaneous autoimmune arthritis in mice. J Clin Invest 114: 582–8PubMedGoogle Scholar
  36. 36.
    Hirota K, Hashimoto M, Yoshitomi H, Tanaka S, Nomura T, Yamaguchi T, Iwakura Y, Sakaguchi N, Sakaguchi S (2007) T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17 Th cells that cause autoimmune arthritis. J Exp Med 204: 41–7PubMedCrossRefGoogle Scholar
  37. 37.
    Sawa S, Kamimura D, Jin GH, Morikawa H, Kamon H, Nishihara M, Ishihara K, Murakami M, Hirano T (2006) Autoimmune arthritis associated with mutated IL-6 receptor gp130 is driven by STAT3/IL-7 dependent homeostatic proliferation of CD4+ T cells. J Exp Med 203: 1459–70PubMedCrossRefGoogle Scholar
  38. 38.
    van den Berg WB, Joosten LA, van de Loo FA (1999) TNFα and IL-1β are separate targets in chronic arthritis. Clin Exp Rheumatol 17 (Suppl 18) S105–114Google Scholar
  39. 39.
    van den Berg WB (2001) Anti-cytokine therapy in chronic destructive arthritis. Arthritis Res Ther 3: 18–26Google Scholar
  40. 40.
    Joosten LA, Abdollahi-Roodsaz S, Heuvelmans M, Helsen MM, van den Bersselaar LA, Oppers-Walgreen B, Koenders MI, van den Berg WB (2008) T cell dependency of chronic destructive arthritis induced by repeated local activation of TLR-driven pathways: Crucial role for both IL-1beta and IL-17. Arthritis Rheum 58: 98–108PubMedCrossRefGoogle Scholar
  41. 41.
    Lubberts E, Schwarzenberger P, Huang W, Schurr JR, Peschon JJ, van den Berg WB, Kolls JK (2005) Requirement of IL-17 receptor signaling in radiation-resistant cells in the joint for full progression of destructive synovitis. J Immunol 175: 3360–68PubMedGoogle Scholar
  42. 42.
    O’Sullivan BJ, Thomas HE, Pai S, Santamaria P, Iwakura Y, Steptoe RJ, Kay TW, Thomas R (2006) IL-1β breaks tolerance through expansion of CD25+ effector cells. J Immunol 176: 7278–87PubMedGoogle Scholar
  43. 43.
    Koenders MI, Lubberts E, van de Loo FA, Oppers-Walgreen B, van den Bersselaar L, Helsen MM, Joosten LA, van den Berg WB (2006) IL-17 acts independently of TNFβ under arthritic conditions. J Immunol 176: 6262–69PubMedGoogle Scholar
  44. 44.
    Choe JY, Crain B, Wu SR, Corr M (2003) IL-1 receptor dependence of serum transferred arthritis can be circumvented by toll-like receptor-4 signaling. J Exp Med 197: 537–42PubMedCrossRefGoogle Scholar
  45. 45.
    Kalliolas GD, Georgiou PE, Antonopoulos IA, Andonopoulos AP, Liossis SN (2007) Anakinra treatment in patients with adult-onset Still’s disease is fast, effective, safe and steroid sparing: Experience from an uncontrolled trial. Ann Rheum Dis 66: 842–3CrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag Basel/Switzerland 2009

Authors and Affiliations

  • Wim B. van den Berg
    • 1
  • Leo A. B. Joosten
    • 1
  • Fons A. J. van de Loo
    • 1
  1. 1.Rheumatology Research & Advanced Therapeutics, Department of RheumatologyRadboud University Nijmegen Medical CentreNijmegenThe Netherlands

Personalised recommendations