Springer Seminars in Immunopathology

, Volume 20, Issue 1–2, pp 133–147 | Cite as

Role of pro-inflammatory cytokines in rheumatoid arthritis

  • Fionula M. Brennan
  • Ravinder N. Maini
  • Marc Feldmann


Rheumatoid arthritis (RA) is well known to be a chronic autoimmune/inflammatory disease which leads to progressive joint damage and destruction. Less well known is the fact that in severe cases of RA, with extra-articular manifestations and multiple joint involvement, there is also a significant reduction in life expectancy [28]. Hence the need for new therapeutic agents. With the cloning of cDNAs encoding cytokines in the early to mid 1980s, it became possible to use new assays to evaluate cytokine expression in the local site of autoimmunity, the rheumatoid synovium. There were two goals. First would understanding cytokine expression help us understand the pathogenesis of RA? Secondly, would it be possible to learn enough about the cytokine network to establish possible therapeutic targets? While a complete understanding of either of these questions remains elusive, here we review the state of knowledge in early 1998, which shows that much progress has been made and that these goals have been partly reached. The clinical benefits of this knowledge are documented elsewhere in this compilation, as is the role of chemokines, anti-inflammatory cytokines and the cytokines involved in neovascularisation.


Rheumatoid Arthritis Arthritis Life Expectancy Therapeutic Target Clinical Benefit 
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.
    Akahoshi T, Wada C, Endo H, Hirota K, Hosaka S, Takagishi K, Konso H, Kashiwazaki S, Matsushima K (1993) Expression of monocyte chemotactic and activating factor in rheumatoid arthritis. Arthritis Rheum 36: 762Google Scholar
  2. 2.
    Alderson MR, Armitage RJ, Tough TW, Strockbine L, Fanslow WC, Spriggs MK (1993) CD40 expression by human monocytes: regulation by cytokines and activation of monocytes by the ligand for CD40. J Exp Med 178: 669Google Scholar
  3. 3.
    Alvaro-Garcia JM, Zvaifler NJ, Firestein GS (1989) Cytokines in chronic inflammatory arthritis. IV. GM-CSF mediated induction of class II MHC antigen on human monocytes: a possible role in RA. J Exp Med 146: 865Google Scholar
  4. 4.
    Arend WP, Dayer JM (1990) Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis. Arthritis Rheum 33: 305Google Scholar
  5. 5.
    Beutler B, Cerami A (1989) The biology of cachectin/TNF - a primary mediator of the host response. Annu Rev Immunol 7: 625Google Scholar
  6. 6.
    Brennan FM, Chantry D, Jackson A, Maim R, Feldmann M (1989) Inhibitory effect of TNF a antibodies on synovial cell interleukin-I production in rheumatoid arthritis. Lancet II: 244Google Scholar
  7. 7.
    Brennan FM, Chantry D, Jackson AM, Maini RN, Feldmann M (1989) Cytokine production in culture by cells isolated from the synovial membrane. J Autoimmun 2 [Suppl]: 177Google Scholar
  8. 8.
    Brennan FM, Chantry D, Turner M, Foxwell B, maim RN, Feldmann M (1990) Transforming growth factor-β in rheumatoid arthritis synovial tissue: lack of effect on spontaneous cytokine production in joint cell cultures. Clin Exp Immunol 81: 278Google Scholar
  9. 9.
    Brennan FM, Zachariae CO, Chantry D, Larsen CG, Turner M, Maim RN, Matsushima K, Feldmann M (1990) Detection of interleukin 8 biological activity in synovial fluids from patients with rheumatoid arthritis and production of interleukin 8 mRNA by isolated synovial cells. Eur J Immunol 20: 2141Google Scholar
  10. 10.
    Bresnihan B, Lookbaugh J, Witt K, Musikic P (1996) Treatment with rIL-Ira in RA: results of a randomised double-blind, placebo-controlled multicentre trial. Arthritis Rheum 39: 5282Google Scholar
  11. 11.
    Bucala R, Ritchin C, Winchester R, Cerami A (1991) Constitutive production of inflammatory and mitogenic cytokines by rheumatoid synovial fibroblasts. J Exp Med 173: 569Google Scholar
  12. 12.
    Buchan G, Barrett K, Fujita T, Taniguchi T, Maim R, Feldmann M (1988) Detection of activated T cell products in the rheumatoid joint using cDNA probes to interleukin-2 (IL-2) IL-2 receptor and IFN-γ. Clin Exp Immunol 71: 295Google Scholar
  13. 13.
    Buchan G, Barrett K, Turner M, Chantry D, Maim RN, Feldmann M (1988) Interleukin-1 and tumour necrosis factor mRNA expression in rheumatoid arthritis: prolonged production of IL-la. Clin Exp Immunol 73: 449Google Scholar
  14. 14.
    Butler DM, Maim RN, Feldmann M, Brennan FM (1995) Modulation of proinflammatory cytokine release in rheumatoid synovial membrane cell cultures. Comparison of monoclonal anti-TNF-a antibody with the IL-1 receptor antagonist. Eur Cytokine Netw 6: 225Google Scholar
  15. 15.
    Campion GV, Lebsack ME, Lookabaugh J, Gordon G, Catalano M, group I-ras (1996) Dose-range and dose frequency study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis. Arthritis Rheum 39: 1092Google Scholar
  16. 16.
    Chantry D, Turner M, Brennan F, Kingsbury A, Feldmann M (1990) Granulocyte-macrophage colony stimulating factor induces both HLA-DR expression and cytokine production by human monocytes. Cytokine 2: 60Google Scholar
  17. 17.
    Charles P, Elliott MJ, Davis D, Potter A, Kalden JR, Antoni C, Breedveld FC, Smolen JS, Eberl G, Woody JN, Feldmann M, Maim RN (1998) Regulation of cytokines and acute phase proteins following TNF-α blockade in rheumatoid arthritis (submitted)Google Scholar
  18. 18.
    Chomarat P, Vannier E, Dechanet J, Rissoan MC, Banchereau J, Dinarello CA, Miossec P (1995) Balance of IL-1 receptor antagonist/IL-1 beta in rheumatoid synovium and its regulation by IL-4 and IL-10. J Immunol 154: 1432Google Scholar
  19. 19.
    Chu CQ, Field M, Abney E, Zheng RQ, Allard S, Feldmann M, Maim RN (1991) Transforming growth factor-β1 in rheumatoid synovial membrane and cartilage/pannus junction. Clin Exp Immunol 86: 380Google Scholar
  20. 20.
    Chu CQ, Field M, Feldmann M, Maim RN (1991) Localization of tumor necrosis factor a in synovial tissues and at the cartilage-pannus junction in patients with rheumatoid arthritis. Arthritis Rheum 34: 1125Google Scholar
  21. 21.
    Cohen SBA, Katsikis PD, Chu CQ, Thomssen H, Webb LMC, Maim RN, Londei M, Feldmann M (1995) High IL-10 production by the activated T cell population within the rheumatoid synovial membrane. Arthritis Rheum 38: 946Google Scholar
  22. 22.
    Cush JJ, Splawski JB, Thomas R, McFarlin JE, Schulze-Koops H, Davis LS, Fujita K, Lipsky PE (1995) Elevated interleukin-10 levels in patients with rheumatoid arthritis. Arthritis Rheum 38: 96Google Scholar
  23. 23.
    Deleuran BW, Chu CQ, Field M, Brennan FM, Katsikis P, Feldmann M, Maim RN (1992) Localization of interleukin-la, type 1 interleukin-1 receptor and interleukin-1 receptor antagonist in the synovial membrane and cartilage/pannus junction in rheumatoid arthritis. Br J Rheumatol 31: 801Google Scholar
  24. 24.
    Di Giovine FS, Nuki G, Duff GW (1988) Tumour necrosis factor in synovial exudates. Ann Rheum Dis 47: 768Google Scholar
  25. 25.
    Eastgate JA, Symons JA, Wood NC, Grinlinton FM, di Giovine FS, Duff GW (1988) Correlation of plasma interleukin 1 levels with disease activity in rheumatoid arthritis. Lancet II: 706Google Scholar
  26. 26.
    Elliott MJ, Maim RN, Feldmann M, Long-Fox A, Charles P, Katsikis P, Brennan FM, Walker J, Bijl H, Ghrayeb J, Woody J (1993) Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to TNF-α. Arthritis Rheum 36: 1681Google Scholar
  27. 27.
    Elliott MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen JS, Leeb B, Breedveld FC, Macfarlane JD, Bijl H, Woody JN (1994) Randomised double blind comparison of a chimaeric monoclonal antibody to tumour necrosis factor α (cA2) versus placebo in rheumatoid arthritis. Lancet 344: 1105Google Scholar
  28. 28.
    Erhardt CC, Mumford PA, Venables PJW, Maim RN (1989) Factors predicting a poor life prognosis in rheumatoid arthritis: an eight year prospective study. Ann Rheum Dis 48: 7Google Scholar
  29. 29.
    Fava RA, Olsen NJ, Postlethwaite AE, Broadley KN, Davidson JM, Nanney LB, Lucas C, Townes AS (1991) Transforming growth factor β1 (TGF-(31) induced neutrophil recruitment to synovial tissues: implications for TGF-β-driven synovial inflammation and hyperplasia. J Exp Med 173: 1121Google Scholar
  30. 30.
    Fava RA, Olsen NJ, Spencer-Green G, Yen KT, Yeo TK, Berse B, Jackman RW, Senger DR, Dvorak HE, Brown LF (1994) Vascular permeability factor/endothelial growth factor (VPF/VEGF): accumulation and expression in human synovial fluids and rheumatoid synovial tissue. J Exp Med 180: 341Google Scholar
  31. 31.
    Feldmann M, Brennan FM, Maini RN (1996) Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 14: 397Google Scholar
  32. 32.
    Fell HB, Jubb RW (1977) The effect of synovial tissue on the breakdown of articular cartilage in organ culture. Arthritis Rheum 20: 1359Google Scholar
  33. 33.
    Field M, Chu C, Feldmann M, Maim RN (1991) Interleukin-6 localisation in the synovial membrane in rheumatoid arthritis. Rheumatol Int 11: 45Google Scholar
  34. 34.
    Firestein GS, Zvaifler NJ (1990) How important are T cells in chronic rheumatoid synovitis? Arthritis Rheum 33: 768Google Scholar
  35. 35.
    Firestein GS, Xu W-D, Townsend K, Broide D, Alvaro-Gracia J, Glasebrook A, Zvaifler NJ (1988) Cytokines in chronic inflammatory arthritis. 1. Failure to detect T cell lymphokines (interleukin 2 and Interleukin 3) and presence of macrophage colony-stimulating factor (CSF-1) and a novel mast cell growth factor in rheumatoid synovitis. J Exp Med 168: 1573Google Scholar
  36. 36.
    Firestein GS, Alvaro-Gracia JM, Maki R (1990) Quantitative analysis of cytokine gene expression in rheumatoid arthritis. J Immunol 144: 3347Google Scholar
  37. 37.
    Firestein GS, Berger AB, Tracey DE, Chosay JG, Chapman DL, Paine MM, Yu C, Zvaifler NJ (1992) IL-1 receptor antagonist protein production and gene expression in rheumatoid arthritis and osteoarthritis synovium. J Immunol 149: 1054Google Scholar
  38. 38.
    Fong Y, Tracey KJ, Moldawer LL, Hesse DG, Manogue KB, Kenney JS, Lee AT, Kuo GC, Allison AC, Lowry SF, Cerami A (1989) Antibodies to cachectin/tumor necrosis factor reduce interleukin 1β and interleukin 6 appearance during lethal bacteremia. J Exp Med 170: 1627Google Scholar
  39. 39.
    Fontana A, Hentgartner H, Fehr K, Grob PJ, Cohen G (1982) Interleukin-1 activity in the synovial fluid of patients with rheumatoid arthritis. Rheumatol Int 2: 49Google Scholar
  40. 40.
    Fouilhoux M, Chabaud M, Fossiez F, Miossec P (1997) Production of IL-17 and its regulation in rheumatoid synovium. Arthritis Rheum 40: S1447Google Scholar
  41. 41.
    Gabay C, Smith MF, Eidlen D, Arend WP (1997) Interleukin 1 receptor antagonist (IL-1Ra) is an acute-phase protein [see comments]. J Clin Invest 99: 2930Google Scholar
  42. 42.
    Goddard DH, Grossman SL, Moore ME (1990) Autocrine regulation of rheumatoid arthritis synovial cell growth in vitro. Cytokine 2: 149Google Scholar
  43. 43.
    Goddard DH, Grossman SL, Williams WV, Weiner DB, Gross JL, Eidsvoog K, Dasch JR (1992) Regulation of synovial cell growth: coexpression of transforming growth factor β and basic fibroblast growth factor by cultured synovial cells. Arthritis Rheum 35: 1296Google Scholar
  44. 44.
    Goeddel DV, Yelverton E, Ullrich A, Heyneker HL, Miozzari G, Holmes W, Seeburg PH, Dull T, May L, Stebbing N, Crea R, Maeda S, McCandliss R, Sloma A, Tabor JM, Gross M, Familletti PC, Pestka S (1980) Human leukocyte interferon produced byE. coli is biologically active. Nature 287: 411Google Scholar
  45. 45.
    Goeddel DV, Leung DW, Dull TJ, Gross M, Lawn RM, McCandliss R, Seeburg PH, Ullrich A, Yelverton E, Gray PW (1981) The structure of eight distinct cloned human leukocyte interferon cDNAs. Nature 290: 20Google Scholar
  46. 46.
    Gowen M, Wood DD, Ihrie EJ, McGuire MKB, Russell RG (1983) An Interleukin-1 like factor stimulates bone resorption in vitro. Nature 306: 378Google Scholar
  47. 47.
    Gray PW, Aggarwal BB, Benton CV, Bringman TS, Henzel WJ, Jarrett JA, Leung DW, Moffat B, Ng P, Svedersky LP, Palladino MA, Nedwin GE (1984) Cloning and expression of cDNA for human lymphotoxin, a lymphokine with tumor necrosis factor activity. Nature 312: 721Google Scholar
  48. 48.
    Hachicha M, Rathanaswami P, Schall TJ, McColl SR (1993) Production of monocyte chemotactic protein-1 in human type B synoviocytes. Synergistic effect of tumor necrosis factor alpha and interferongamma. Arthritis Rheum 36: 26Google Scholar
  49. 49.
    Haworth C, Brennan FM, Chantry D, Turner M, Maim RN, Feldmann M (1991) Expression of granulocyte-macrophage colony-stimulating factor in rheumatoid arthritis: regulation by tumor necrosis factor-α. Eur J Immunol 21: 2575Google Scholar
  50. 50.
    Haworth C, Brennan FM, Chantry D, Turner M, Maim RN, Feldmann M (1991) Expression of granulocyte-macrophage colony-stimulating factor in rheumatoid arthritis: regulation by tumor necrosis factor-alpha. Eur J Immunol 21: 2575Google Scholar
  51. 51.
    Helle M, Boeije L, Groot E de, Vos A de, Aarden L (1991) Detection of IL-6 in biological fluids: synovial fluids and sera. J Immunol Methods 138: 47Google Scholar
  52. 52.
    Hermann J, Hall M, Maim R, Feldmann M, Brennan F (1998) Important immunmegulatory role of interleukin-11 in the inflammatory process in rheumatoid arthritis. Arthritis Rheum (in press)Google Scholar
  53. 53.
    Hirano T, Matsuda T, Turner M, Miyasaka N, Buchan G, Tang B, Sato K, Shimizu M, Maim R, Feldmann M, Kishimoto T (1988) Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis. Eur J Immunol 18: 1797Google Scholar
  54. 54.
    Hopkins SJ, Meager A (1988) Cytokines in synovial fluid. II. The presence of tumour necrosis factor and interferon. Clin Exp Immunol 73: 88Google Scholar
  55. 55.
    Hopkins SJ, Humphreys M, Jayson MI (1988) Cytokines in synovial fluid. I. The presence of biologically active and immunoreactive IL-1. Clin Exp Immunol 72: 422Google Scholar
  56. 56.
    Hosaka S, Akshoshi T, Wada C, Kondo H (1994) Expression of the chemokine superfamily in rheumatoid arthritis. Clin Exp Immunol 97: 451Google Scholar
  57. 57.
    Houssiau FA, Devogelaer J-P, Damme J van, Nagant de Deuxchaisnes C, Snick J van (1988) Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides. Arthritis Rheum 31: 784Google Scholar
  58. 58.
    Isler P, Vey E, Zhang JH, Dayer JM (1993) Cell surface glycoproteins expressed on activated human T cells induce production of interleukin-1 beta by monocytic cells: a possible role of CD69. Eur Cytokine Netw 4: 15Google Scholar
  59. 59.
    Isomaki P, Luukkainen R, Toivanen P, Punnonen J (1996) The presence of interleukin-13 in rheumatoid synovium and its antiinflammatory effects on synovial fluid macrophages from patients with rheumatoid arthritis. Arthritis Rheum 39: 1693Google Scholar
  60. 60.
    Joosten LA, Helsen MM, Loo FA van de, Berg WB van den (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: 797Google Scholar
  61. 61.
    Katsikis PD, Chu CQ, Brennan FM, Maini RN, Feldmann M (1994) Immunoregulatory role of interleukin 10 in rheumatoid arthritis. J Exp Med 179: 1517Google Scholar
  62. 62.
    Keffer J, Probert L, Cazlaris H, Georgopoulos S, Kaslaris E, Kioussis D, Kollias G (1991) Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J 10: 4025Google Scholar
  63. 63.
    Kiener PA, Moran-Davis P, Rankin BM, Wahl AF, Aruffo A, Hollenbaugh D (1995) Stimulation of CD40 with purified soluble gp39 induces proinflammatory responses in human monocytes. J Immunol 155: 4917Google Scholar
  64. 64.
    Kirkham B, Portek I, Lenarcyzk A, Stavros B, Edmonds J (1997) Interleukin 17 mRNA expression in rheumatoid and psoriatic arthritis synovial membrane. Arthritis Rheum 40: S 1006Google Scholar
  65. 65.
    Koch AE, Kunkel SL, Burrows JC, Evanoff HL, Haines GK, Pope RM, Stricter RM (1991) Synovial tissue macrophage as a source of the chemotactic cytokine IL-8. J Immunol 147: 2187Google Scholar
  66. 66.
    Koch AE, Kunkel SL, Harlow LA, Johnson B, Evanoff HL, Haines GK, Burdick MD, Pope RM, Stricter RM (1992) Enhanced production of monocyte chemoattractant protein-1 in rheumatoid arthritis. J Clin Invest 90: 772Google Scholar
  67. 67.
    Koch AE, Kunkel SL, Pearce WH, Shah MR, Parikh D, Evanoff HL, Haines GK, Burdick MD, Strieter RM (1993) Enhanced production of the chemotactic cytokines interleukin-8 and monocyte chemoattractant protein-1 in human abdominal aortic aneurysms. Am J Pathol 142: 1423Google Scholar
  68. 68.
    Koch AE, Kunkel SL, Harlow LA, Mazarakis DD, Haines GK, Burdick MD, Pope RM, Stricter RM (1994) Macrophage inflammatory protein-1 alpha. A novel chemotactic cytokine for macrophages in rheumatoid arthritis. J Clin Invest 93: 921Google Scholar
  69. 69.
    Koch AE, Kunkel SL, Harlow LA, Mazarakis DD, Haines GK, Burdick MD, Pope RM, Walz A, Strieter RM (1994) Epithelial neutrophil activating peptide-78: a novel chemotactic cytokine for neutrophils in arthritis. J Clin Invest 94: 1012Google Scholar
  70. 70.
    Koch AE, Harlow LA, Haines GK, Amento EP, Unemori EN, Wong WL, Pope RM, Ferrara N (1994) Vascular endothelial growth factor. A cytokine modulating endothelial function in rheumatoid arthritis. J Immunol 152: 4149Google Scholar
  71. 71.
    Laffon A, Garcia-Vicuna R, Humbria A, Postigo AA, Corbi AL, Landazuri MO de, Sanchez-Madrid F (1991) Upregulated expression and function of VLA-4 fibronectin receptors on human activated T cells in rheumatoid arthritis. J Clin Invest 88: 546Google Scholar
  72. 72.
    Lafyatis R, Thomson NL, Remmers ER, Flanders KC, Roche NS, Kim SJ (1989) Transforming growth factor-beta production by synovial tissues from rheumatoid patients and streptococcal cell wall arthritis rats. Studies on secretion by synovial fibroblast-like cells and immunohistological localisation. J Immunol 143: 1142Google Scholar
  73. 73.
    Llorente L, Richaud-Patin Y, Fior R, Alcocer-Varela J, Wijdenes J, Fourrier B, Galanaud P, Emilie D (1994) In vivo production of interleukin-10 by non-T cells in rheumatoid arthritis, Sjogren's syndrome, and systemic lupus erythematosus. Arthritis Rheum 37: 1647Google Scholar
  74. 74.
    Lotz M, Kekow J, Carson DA (1990) Transforming growth factor-β and cellular immune responses in synovial fluids. J Immunol 144: 4189Google Scholar
  75. 75.
    Lotz M, Moats T, Villeger PM (1992) Leukemia inhibitory factor is expressed in cartilage and synovium and can contribute to the pathogenesis of arthritis. J Clin Invest 90: 888Google Scholar
  76. 76.
    Maini RN, Paulus H, Breedveld FC, Moreland LW, William E, Russell AS, Charles P, Davies D, Grint P, Wherry JC, Feldmann M (1997) rHUIL-10 in subjects with active rheumatoid arthritis (RA): a phase I and cytokine response study. Arthritis Rheum 40 (Suppl): 5224Google Scholar
  77. 77.
    Maini RN, Breedveld FC, Kalden JR, Smolen IS, Davis D, Macfarlane JD, Antoni C, Leeb B, Elliott MJ, Woody JN, Schaible TF, Feldmann M (1998) Randomized placebo-controlled trial of multiple intravenous infusions of anti-TNF-a monoclonal antibody with or without weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 41:1152Google Scholar
  78. 78.
    Malfait AM, Butler DM, Presky DH, Maini RN, Brennan FM, Feldmann M (1998) Blockade of IL-12 during the induction of collagen-induced arthritis (CIA) markedly attenuates the severity of the arthritis. Clin Exp Immunol 111: 377Google Scholar
  79. 79.
    Manie S, Kubar J, Limouse M, Ferrua B, Ticchioni M, Breittmayer JP, Peyron JF, Schaffar L, Rossi B (1993) CD3-stimulated Jurkat T cells mediate IL-1 beta production in monocytic THP-1 cells. Role of LFA-1 molecule and participation of CD69 T cell antigen. Eur Cytokine Netw 4: 7Google Scholar
  80. 80.
    McInnes IB, al-Mughales J, Field M, Levnq BP, Hveng FP, Dixon R, Sturrock RD, Wilkinson PC, Lieu KY (1996) The role of interleukin 15 in T-cell migration and activation in RA. Nat Med 2:175Google Scholar
  81. 81.
    Miossec P, Naviliat M, D'Angeac AD, Sany J, Banchereau J (1990) Low levels of interleukin-4 and high levels of transforming growth factor β in rheumatoid synovitis. Arthritis Rheum 33: 1180Google Scholar
  82. 82.
    Morita Y, Yamamura M, Nishida K, Harada S, Okamoto H, Inoue H, Ohmoto Y, Modlin RL, Makino H (1998) Expression of interleukin-12 in synovial tissue from patients with rheumatoid arthritis. Arthritis Rheum 41: 306Google Scholar
  83. 83.
    Nagata S, Taira H, Hall A, Johnsrud L, Streuli M, Ecsodi J, Boll W, Cantell K, Weissmann C (1980) Synthesis inE. coli of a polypeptide with human leukocyte interferon activity. Nature 284: 316Google Scholar
  84. 84.
    Nawroth PP, Bank I, Handley D, Cassimeris J, Chess L, Stern D (1986) Tumor necrosis factor/cachectin interacts with endothelial cell receptors to induce release of interleukin 1. J Exp Med 163: 1363Google Scholar
  85. 85.
    Okamoto H, Yamamura M, Morita Y, Harada S, Makino H, Ota Z (1997) The synovial expression and serum levels of interleukin-6, interleukin- 11, leukemia inhibitory factor, and oncostatin M in rheumatoid arthritis. Arthritis Rheum 40: 1096Google Scholar
  86. 86.
    Piguet PF, Grau GE, Uesin C, Loetscher H, Gentz R, Lesslauer W (1992) Evolution of collagen arthritis in mice is arrested by treatment with anti-tumour necrosis factor (TNF) antibody or a recombinant soluble TNF receptor. Immunology 77: 510Google Scholar
  87. 87.
    Probert L, Plows D, Kontogeorgos G, Kollias G (1995) The type 1 interleukin-1 receptor acts in series with tumor necrosis factor (TNF) to induce arthritis in TNF- transgenic mice. Eur J Immunol 25: 1794Google Scholar
  88. 88.
    Rathanaswami P, Hachicha M, Sadick M, Schall TJ, McColl SR (1993) Expression of the cytokine RANTES in human rheumatoid synovial fibroblasts. Differential regulation of RANTES and interleukin-8 genes by inflammatory cytokines. J Biol Chem 268: 5834Google Scholar
  89. 89.
    Remmers EF, Lafyatis R, Kumkumian GK, Case JP, Roberts AB, Spron MB, Wilder RL (1990) Cytokines and growth regulation of synoviocytes from patients with rheumatoid arthritis and rats with streptococcal cell wall arthritis. Growth Factors 2: 179Google Scholar
  90. 90.
    Remmers EF, Sano H, Lafyatis R, Case JP, Kumkumian GK, Hla T, Maciag T, Wilder R (1991) Production of platelet derived growth factor B chain (PDGF-B/c-sis) mRNA and immunoreactive PDGF B-like polypeptide by rheumatoid synovium: coexpression with heparin binding acidic fibroblast growth factor-1. J Rheumatol 18: 7Google Scholar
  91. 91.
    Rogge L, Barberis-Maino L, Biffi M, Passini N, Presky DH, Gubler U, Sinigaglia F (1997) Selective expression of an interleukin-12 receptor component by human T helper 1 cells. J Exp Med 185: 825Google Scholar
  92. 92.
    Saklatvala J, Sarsfield SJ, Townsend Y (1985) Purification of two immunologically different leucocyte proteins that cause cartilage resorption lymphocyte activation and fever. J Exp Med 162: 1208Google Scholar
  93. 93.
    Sano H, Forough R, Maier JA, Case JP, Jackson A, Engleka K, Maciag T, Wilder RL (1990) Detection of high levels of heparin binding growth factor-1 (acidic fibroblast growth factor) in inflammatory arthritic joints. J Cell Biol 110: 1417Google Scholar
  94. 94.
    Sano H, Engleka K, Mathern P, Hla T, Crofford LJ, Remmers EF, Jelsema CL, Goldmuntz E, Maciag T, Wilder RL (1993) Coexpression phosphotyrosine-containing proteins, platelet-derived growth factor-B, and fibroblast growth factor-1 in situ in synovial tissues of patients with rheumatoid arthritis and Lewis rats with adjuvant or streptococcal cell wall arthritis. J Clin Invest 91: 553Google Scholar
  95. 95.
    Saxne T, Palladino MA, Jr., Heinegard D, Talal N, Wollheim FA (1988) Detection of tumor necrosis factor a but not tumor necrosis factor β in rheumatoid arthritis synovial fluid and serum. Arthritis Rheum 31: 1041Google Scholar
  96. 96.
    Sebbag M, Parry SL, Brennan FM, Feldmann M (1997) Cytokine stimulation of T lymphocytes regulates their capacity to induce monocyte production of TNF-α but not IL-10: possible relevance to pathophysiology of rheumatoid arthritis. Eur J Immunol 27: 624Google Scholar
  97. 97.
    Shu U, Kiniwa M, Wu CY, Maliszewski C, Vezzio N, Hakimi J, Gately M, Delespesse G (1995) Activated T cells induce interleukin-12 production by monocytes via CD40-CD40 ligand interaction. Eur J Immunol 25: 1125Google Scholar
  98. 98.
    Taga T, Hibi M, Hirata Y, Yamasaki K, Yasukawa K, Matsuda T, Hirano T, Kishimoto T (1989) Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell 58: 573Google Scholar
  99. 99.
    Taki H, Sugiyama E, Mino T, Kuroda A, Kobayashi M (1998) Differential inhibitory effects of indomethacin, dexamethasone, and interferon-gamma (IFN-gamma) on IL- l 1 production by rheumatoid synovial cells. Clin Exp Immunol 112: 133Google Scholar
  100. 100.
    Taniguchi T, Matsui H, Fujita T, Takaoka C, Kashima N, Yoshimoto R, Hamuro J (1983) Structure and expression of a cloned cDNA for human interleukin-2. Nature 302: 305Google Scholar
  101. 101.
    Thorbecke GJ, Shah R, Leu CH, Kuruvilla AP, Hardison AM, Palladino MA (1992) Involvement of endogenous tumour necrosis factor α and transforming growth factor β during induction of collagen type II arthritis in mice. Proc Natl Acad Sci USA 89: 7375Google Scholar
  102. 102.
    Trepicchio WL, Bozza M, Pedneault G, Dorner AJ (1996) Recombinant human interleukin-11 attenuates the inflammatory response through down-regulation of proinflammatory cytokine release and nitric oxide production. J Immunol 157: 3627Google Scholar
  103. 103.
    Ulfgren AK, Lindblad S, Klareskog L, Andersson J, Andersson U (1995) Detection of cytokine producing cells in the synovial membrane from patients with rheumatoid arthritis. Ann Rheum Dis 54: 654Google Scholar
  104. 104.
    Villiger PM, Terkeltaub R, Lutz M (1992) Production of monocyte chemoattractant protein-1 by inflamed synovial tissue and cultured synoviocytes. J Immunol 149: 722Google Scholar
  105. 105.
    Wagner D Jr, Stout RD, Suttles J (1994) Role of the CD40-CD40 ligand interaction in CD4' T cell contact-dependent activation of monocyte interleukin-1 synthesis. Eur J Immunol 24: 3148Google Scholar
  106. 106.
    Wang AM, Creasey AA, Ladner MB, Lin LS, Strickler J, Van Arsdell JN, Yamamoto R, Mark DF (1985) Molecular cloning of the complementary DNA for human tumor necrosis factor. Science 228: 149Google Scholar
  107. 107.
    Waring PM, Carroll GJ, Kandiah DA, Buirski G, Metcalf D (1993) Increased levels of leukemia inhibitory factor in synovial fluid from patients with rheumatoid arthritis and other inflammatory arthritides. Arthritis Rheum 36: 911Google Scholar
  108. 108.
    Wendling D, Racadot E, Wijdenes J (1993) Treatment of severe rheumatoid arthritis by anti-interleukin 6 monoclonal antibody. J Rheumatol 20: 259Google Scholar
  109. 109.
    Wijdenes J, Racadot E, Wendling D (1994) Interleukin 6 antibodies in rheumatoid arthritis. J Interferon Res 14: 297Google Scholar
  110. 110.
    Williams RO, Feldmann M, Maini RN (1992) Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. Proc Natl Acad Sci USA 89: 9784Google Scholar
  111. 111.
    Williams RO, Mason LJ, Feldmann M, Maim RN (1994) Synergy between anti-CD4 and anti-TNF in the amelioration of established collagen-induced arthritis. Proc Natl Acad Sci USA 91: 2762Google Scholar
  112. 112.
    Williams RO, Ghrayeb J, Feldmann M, Maim RN (1995) Successful therapy of collagen-induced arthritis with TNF receptor-IgG fusion protein and combination with anti-CD4. Immunology 84: 433Google Scholar
  113. 113.
    Williams RO, Mauri C, Mason L, Marinova-Mutafchieva L, Ross S, Feldmann M, Maim R (1998) Mechanisms of action of cyclosporin and anti-TNF-a in collagen-induced arthritis and effect of combination therapy. Arthritis Rheum (in press)Google Scholar
  114. 114.
    Wood NC, Dickens E, Symons JA, Duff GW (1992) In situ hybridization of interleukin-1 in CD14positive cells in rheumatoid arthritis. Clin Immunol Immunopathol 62: 295Google Scholar
  115. 115.
    Wooley PH, Whalen JD, Chapman DL, Berger AE, Richard KA, Aspar DG, Staite ND (1993) The effect of an interleukin-I receptor antagonist protein on type II collage-induced arthritis and antigen-induced arthritis in mice. Arthritis Rheum 36: 1305Google Scholar
  116. 116.
    Xu WD, Firestein GS, Taetle R, Kaushansky K, Zvaifler NJ (1989) Cytokines in chronic inflammatory arthritis. II. Granulocyte-macrophage colony-stimulating factor in rheumatoid synovial effusions. J Clin Invest 83: 876Google Scholar
  117. 117.
    Yamamura M, Kawashima M, Morita Y, Makino H, Tanimoto T, Kurimoto M (1997) Increased production of interleukin-18 in synovium from patients with rheumatoid arthritis. Arthritis Rheum 40: S 1459Google Scholar

Copyright information

© Springer-Verlag 1998

Authors and Affiliations

  • Fionula M. Brennan
    • 1
  • Ravinder N. Maini
    • 1
  • Marc Feldmann
    • 1
  1. 1.Kennedy Institute of RheumatologyHammersmithUK

Personalised recommendations