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Logo of annrheumdAnnals of the Rheumatic DiseasesCurrent TOCInstructions for authors
Ann Rheum Dis. Nov 1999; 58(Suppl 1): I40–I48.
PMCID: PMC1766568

Role of tumour necrosis factor α in experimental arthritis: separate activity of interleukin 1β in chronicity and cartilage destruction


Chronic arthritis is characterised by persistent joint inflammation and concomitant joint destruction. Using murine arthritis models and neutralising antibodies as well as cytokine specific knockout conditions, it was found that tumour necrosis factor α (TNFα) is important in early joint swelling. Membrane bound TNFα is sufficient to drive this aspect of inflammation as well as the acute cellular infiltrate in the synovial tissue. Interleukin 1 (IL1) is not necessarily a dominant cytokine in early joint swelling, but has a pivotal role in sustained cellular infiltration and erosive cartilage damage. TNFα independent IL1 production is a prominent feature in murine arthritis models. These observations provide evidence for potential uncoupling of joint inflammation and erosive changes, implying that both cytokines need to be targeted to achieve optimal treatment.

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Selected References

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  • Firestein GS, Zvaifler NJ. How important are T cells in chronic rheumatoid synovitis? Arthritis Rheum. 1990 Jun;33(6):768–773. [PubMed]
  • Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol. 1996;14:397–440. [PubMed]
  • Arend WP, Dayer JM. Inhibition of the production and effects of interleukin-1 and tumor necrosis factor alpha in rheumatoid arthritis. Arthritis Rheum. 1995 Feb;38(2):151–160. [PubMed]
  • Keffer J, Probert L, Cazlaris H, Georgopoulos S, Kaslaris E, Kioussis D, Kollias G. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J. 1991 Dec;10(13):4025–4031. [PMC free article] [PubMed]
  • Bresnihan B, Alvaro-Gracia JM, Cobby M, Doherty M, Domljan Z, Emery P, Nuki G, Pavelka K, Rau R, Rozman B, et al. Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum. 1998 Dec;41(12):2196–2204. [PubMed]
  • Saklatvala J. Tumour necrosis factor alpha stimulates resorption and inhibits synthesis of proteoglycan in cartilage. Nature. 1986 Aug 7;322(6079):547–549. [PubMed]
  • 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 Apr;49(4):238–245. [PMC free article] [PubMed]
  • Henderson B, Pettipher ER. Arthritogenic actions of recombinant IL-1 and tumour necrosis factor alpha in the rabbit: evidence for synergistic interactions between cytokines in vivo. Clin Exp Immunol. 1989 Feb;75(2):306–310. [PMC free article] [PubMed]
  • 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 May;42(5):963–970. [PubMed]
  • Ghivizzani SC, Kang R, Georgescu HI, Lechman ER, Jaffurs D, Engle JM, Watkins SC, Tindal MH, Suchanek MK, McKenzie LR, et al. Constitutive intra-articular expression of human IL-1 beta following gene transfer to rabbit synovium produces all major pathologies of human rheumatoid arthritis. J Immunol. 1997 Oct 1;159(7):3604–3612. [PubMed]
  • 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 Jun;25(6):1794–1797. [PubMed]
  • Kontoyiannis D, Pasparakis M, Pizarro TT, Cominelli F, Kollias G. Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity. 1999 Mar;10(3):387–398. [PubMed]
  • Mauri C, Williams RO, Walmsley M, Feldmann M. Relationship between Th1/Th2 cytokine patterns and the arthritogenic response in collagen-induced arthritis. Eur J Immunol. 1996 Jul;26(7):1511–1518. [PubMed]
  • Joosten LA, Lubberts E, Durez P, Helsen MM, Jacobs MJ, Goldman M, van den Berg WB. Role of interleukin-4 and interleukin-10 in murine collagen-induced arthritis. Protective effect of interleukin-4 and interleukin-10 treatment on cartilage destruction. Arthritis Rheum. 1997 Feb;40(2):249–260. [PubMed]
  • 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 Oct 15;159(8):4094–4102. [PubMed]
  • Marinova-Mutafchieva L, Williams RO, Mason LJ, Mauri C, Feldmann M, Maini RN. Dynamics of proinflammatory cytokine expression in the joints of mice with collagen-induced arthritis (CIA). Clin Exp Immunol. 1997 Mar;107(3):507–512. [PubMed]
  • 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 Oct 15;89(20):9784–9788. [PMC free article] [PubMed]
  • Wooley PH, Dutcher J, Widmer MB, Gillis S. Influence of a recombinant human soluble tumor necrosis factor receptor FC fusion protein on type II collagen-induced arthritis in mice. J Immunol. 1993 Dec 1;151(11):6602–6607. [PubMed]
  • van den Berg WB, Joosten LA, Helsen M, van de Loo FA. Amelioration of established murine collagen-induced arthritis with anti-IL-1 treatment. Clin Exp Immunol. 1994 Feb;95(2):237–243. [PMC free article] [PubMed]
  • Joosten LA, Helsen MM, van de Loo FA, van den Berg WB. 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. 1996 May;39(5):797–809. [PubMed]
  • Ku G, Faust T, Lauffer LL, Livingston DJ, Harding MW. Interleukin-1 beta converting enzyme inhibition blocks progression of type II collagen-induced arthritis in mice. Cytokine. 1996 May;8(5):377–386. [PubMed]
  • Bendele A, McAbee T, Sennello G, Frazier J, Chlipala E, McCabe D. Efficacy of sustained blood levels of interleukin-1 receptor antagonist in animal models of arthritis: comparison of efficacy in animal models with human clinical data. Arthritis Rheum. 1999 Mar;42(3):498–506. [PubMed]
  • Bakker AC, Joosten LA, Arntz OJ, Helsen MM, Bendele AM, van de Loo FA, van den Berg WB. Prevention of murine collagen-induced arthritis in the knee and ipsilateral paw by local expression of human interleukin-1 receptor antagonist protein in the knee. Arthritis Rheum. 1997 May;40(5):893–900. [PubMed]
  • Pasparakis M, Alexopoulou L, Episkopou V, Kollias G. Immune and inflammatory responses in TNF alpha-deficient mice: a critical requirement for TNF alpha in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response. J Exp Med. 1996 Oct 1;184(4):1397–1411. [PMC free article] [PubMed]
  • Alexopoulou L, Pasparakis M, Kollias G. Complementation of lymphotoxin alpha knockout mice with tumor necrosis factor-expressing transgenes rectifies defective splenic structure and function. J Exp Med. 1998 Aug 17;188(4):745–754. [PMC free article] [PubMed]
  • Mori L, Iselin S, De Libero G, Lesslauer W. Attenuation of collagen-induced arthritis in 55-kDa TNF receptor type 1 (TNFR1)-IgG1-treated and TNFR1-deficient mice. J Immunol. 1996 Oct 1;157(7):3178–3182. [PubMed]
  • Van Lent PL, Van De Loo FA, Holthuysen AE, Van Den Bersselaar LA, Vermeer H, Van Den Berg WB. Major role for interleukin 1 but not for tumor necrosis factor in early cartilage damage in immune complex arthritis in mice. J Rheumatol. 1995 Dec;22(12):2250–2258. [PubMed]
  • Kassiotis G, Pasparakis M, Kollias G, Probert L. TNF accelerates the onset but does not alter the incidence and severity of myelin basic protein-induced experimental autoimmune encephalomyelitis. Eur J Immunol. 1999 Mar;29(3):774–780. [PubMed]
  • van de Loo FA, Joosten LA, van Lent PL, Arntz OJ, van den Berg WB. Role of interleukin-1, tumor necrosis factor alpha, and interleukin-6 in cartilage proteoglycan metabolism and destruction. Effect of in situ blocking in murine antigen- and zymosan-induced arthritis. Arthritis Rheum. 1995 Feb;38(2):164–172. [PubMed]
  • Lubberts E, Joosten LA, Helsen MM, van den Berg WB. Regulatory role of interleukin 10 in joint inflammation and cartilage destruction in murine streptococcal cell wall (SCW) arthritis. More therapeutic benefit with IL-4/IL-10 combination therapy than with IL-10 treatment alone. Cytokine. 1998 May;10(5):361–369. [PubMed]
  • Kuiper S, Joosten LA, Bendele AM, Edwards CK, 3rd, Arntz OJ, Helsen MM, Van de Loo FA, Van den Berg WB. Different roles of tumour necrosis factor alpha and interleukin 1 in murine streptococcal cell wall arthritis. Cytokine. 1998 Sep;10(9):690–702. [PubMed]
  • Zheng H, Fletcher D, Kozak W, Jiang M, Hofmann KJ, Conn CA, Soszynski D, Grabiec C, Trumbauer ME, Shaw A, et al. Resistance to fever induction and impaired acute-phase response in interleukin-1 beta-deficient mice. Immunity. 1995 Jul;3(1):9–19. [PubMed]
  • Georgopoulos S, Plows D, Kollias G. Transmembrane TNF is sufficient to induce localized tissue toxicity and chronic inflammatory arthritis in transgenic mice. J Inflamm. 1996;46(2):86–97. [PubMed]
  • Lens JW, van den Berg WB, van de Putte LB, Zwarts WA. Flare of antigen-induced arthritis in mice after intravenous challenge. Kinetics of antigen in the circulation and localization of antigen in the arthritic and noninflamed joint. Arthritis Rheum. 1986 May;29(5):665–674. [PubMed]
  • van de Loo AA, Arntz OJ, Bakker AC, van Lent PL, Jacobs MJ, van den Berg WB. Role of interleukin 1 in antigen-induced exacerbations of murine arthritis. Am J Pathol. 1995 Jan;146(1):239–249. [PMC free article] [PubMed]
  • van de Loo AA, Arntz OJ, van den Berg WB. Flare-up of experimental arthritis in mice with murine recombinant IL-1. Clin Exp Immunol. 1992 Feb;87(2):196–202. [PMC free article] [PubMed]
  • Makarov SS, Olsen JC, Johnston WN, Anderle SK, Brown RR, Baldwin AS, Jr, Haskill JS, Schwab JH. Suppression of experimental arthritis by gene transfer of interleukin 1 receptor antagonist cDNA. Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):402–406. [PMC free article] [PubMed]
  • Marino MW, Dunn A, Grail D, Inglese M, Noguchi Y, Richards E, Jungbluth A, Wada H, Moore M, Williamson B, et al. Characterization of tumor necrosis factor-deficient mice. Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):8093–8098. [PMC free article] [PubMed]
  • Fantuzzi G, Ku G, Harding MW, Livingston DJ, Sipe JD, Kuida K, Flavell RA, Dinarello CA. Response to local inflammation of IL-1 beta-converting enzyme- deficient mice. J Immunol. 1997 Feb 15;158(4):1818–1824. [PubMed]
  • Labow M, Shuster D, Zetterstrom M, Nunes P, Terry R, Cullinan EB, Bartfai T, Solorzano C, Moldawer LL, Chizzonite R, et al. Absence of IL-1 signaling and reduced inflammatory response in IL-1 type I receptor-deficient mice. J Immunol. 1997 Sep 1;159(5):2452–2461. [PubMed]
  • Watson RW, Rotstein OD, Parodo J, Bitar R, Marshall JC, William R, Watson G. The IL-1 beta-converting enzyme (caspase-1) inhibits apoptosis of inflammatory neutrophils through activation of IL-1 beta. J Immunol. 1998 Jul 15;161(2):957–962. [PubMed]
  • van Meurs JB, van Lent PL, Holthuysen AE, Singer II, Bayne EK, van den Berg WB. Kinetics of aggrecanase- and metalloproteinase-induced neoepitopes in various stages of cartilage destruction in murine arthritis. Arthritis Rheum. 1999 Jun;42(6):1128–1139. [PubMed]
  • van Meurs JB, van Lent PL, Singer II, Bayne EK, van de Loo FA, van den Berg WB. Interleukin-1 receptor antagonist prevents expression of the metalloproteinase-generated neoepitope VDIPEN in antigen-induced arthritis. Arthritis Rheum. 1998 Apr;41(4):647–656. [PubMed]
  • Burger D, Rezzonico R, Li JM, Modoux C, Pierce RA, Welgus HG, Dayer JM. Imbalance between interstitial collagenase and tissue inhibitor of metalloproteinases 1 in synoviocytes and fibroblasts upon direct contact with stimulated T lymphocytes: involvement of membrane-associated cytokines. Arthritis Rheum. 1998 Oct;41(10):1748–1759. [PubMed]
  • Brennan FM, Chantry D, Jackson A, Maini R, Feldmann M. Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet. 1989 Jul 29;2(8657):244–247. [PubMed]
  • Deleuran BW. Cytokines in rheumatoid arthritis. Localization in arthritic joint tissue and regulation in vitro. Scand J Rheumatol Suppl. 1996;104:1–34. [PubMed]
  • Kirkham B, Portek I, Lee CS, Stavros B, Lenarczyk A, Lassere M, Edmonds J. Intraarticular variability of synovial membrane histology, immunohistology, and cytokine mRNA expression in patients with rheumatoid arthritis. J Rheumatol. 1999 Apr;26(4):777–784. [PubMed]

Figures and Tables

Figure 1
Treatment of collagen arthritis with TNF binding protein or anti-IL1α+β antibodies, starting at various days after onset of arthritis (arrows). Note the loss of effect in established disease with TNFbp and the continued effect of anti-IL1 ...
Figure 2
COMP levels in the serum at day 38 of collagen arthritis. After treatment with TNFbp no reduction is seen, whereas reduction to normal levels (line) is observed after anti-IL1α+β treatment.
Figure 3
Dose dependent suppression of joint swelling with anti-TNFα or TNFbp. Start of systemic treatment shortly before induction of SCW arthritis, measurements of joint swelling at day 2. (See reference 34 for further reading).
Figure 4
Joint swelling at days 1 and 2 after induction of SCW arthritis in knockouts and their respective controls (NN for IL1β -/-, WT for TNFα -/-). Note the TNFα dependency of joint swelling. Similar studies in mTNFki, ...
Figure 5
Cellular infiltrate is markedly reduced in SCW arthritis (day 7) in TNFα -/- mice (B). However, the Safranin O staining shows that there is considerable loss of proteoglycans (reduced staining) in both control (A) and TNF-/- (B).
Figure 6
Proteoglycan depletion as measured on histological sections (see fig 5) stained with Safranin O at days 4 and 7 after induction of SCW arthritis. Scoring is semiquantitative on a scale of 0-3. Note the significant reduction of depletion ...
Figure 7
Chronic relapsing SCW arthritis induced by repeated injection of SCW fragments in the knee joint. Four groups of mice were flared either at day 7, days 7,14 or days 7,14,21. Chronicity increases after every rechallenge.
Figure 8
Experiments described under figure 7 were performed in the various cytokine-/- mice in the repeated flare protocol (days 7,14,21). Note that arthritis is roughly similar at day 21. The fourth injection of SCW fragments at day 21 caused ...
Figure 9
Histological examination of the knee at day 28 of relapsing SCW arthritis (see figure 8). Safranin O staining shows loss of proteoglycans from the cartilage surface layer in the controls (A) and the TNFα -/- mice (B). In contrast, IL1β ...

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