Attenuation of Inflammatory Disease by Reduction of Interleukin-1 Production or Receptor Antagonism

  • C. A. Dinarello
Conference paper
Part of the Colloquium der Gesellschaft für Biologische Chemie 11.–13. April 1991 in Mosbach/Baden book series (MOSBACH, volume 42)


Interleukin-1 (IL-1) is a 17-kDa pro-inflammatory cytokine synthesized from a variety of cell types primarily in association with disease states or during host perturbation such as immune responses. At pM or even fM concentrations, IL-1 triggers various responses in nearly all cells. It appears that there is little or no major role for IL-1 in homeostatic mechanisms. There are two IL-l’s (α and β) each with its distinct sequence; there are two IL-1 receptors. Disease states such as local and systemic infection, septic shock, degenerative arthritis, and autoimmune diseases such as nephritis, vasculitis, and inflammatory bowel disease appear to be mediated, in part, by IL-1. Organ failure, capillary leak, and death occur in animals after a combination of tumor necrosis factor (TNF) and EL-1 which is more effective in inducing these changes than either cytokine alone. IL-1 is also a potent inducer of the endothelial cell adhesion molecules, IL-6, and IL-8, a neutrophil chemotactic and activating factor. Strategies for reducing the effects of IL-1 have been based on suppression of transcription, translation, or secretion; more recently, receptor blockade has been a new approach. A naturally occurring IL-l-specific receptor antagonist (IL-lra), which shares 40% conserved amino acid homology with IL-lb, binds to IL-1 surface receptors with the same affinity as IL-1 but does not possess agonist activity and acts as a competitive inhibitor of IL-1. Studies using the IL-lra to block endogenous IL-1 in a variety of animal disease models suggest that IL-1 plays a key role in triggering the cascade of inflammatory responses. In addition, the IL-lra reduces the spontaneous production of growth factors and proliferation of leukemic cells. The IL-lra may be an advantageous therapy in patients with sepsis, diabetes, inflammatory bowel disease, arthritis, and cancer.


Cytokine Synthesis Lipoxygenase Product Myelogenous Leukemia Cell Tumor Necrosis Factor Synthesis Separate Gene Product 
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.


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  1. 1.
    Dinarello CA (1991) Blood 77:1627–1652PubMedGoogle Scholar
  2. 2.
    Auron PE, Webb AC, Rosenwasser U, Mucci SF, Rich A, Wolff SM, Dinarello CA (1984) Proc Natl Acad Sci USA 81:7907–7911PubMedCrossRefGoogle Scholar
  3. 3.
    Lomedico PT, Gubler R, Hellmann CP, Dukovich M, Giri JG, Pan YE, CoUier K, Semionow R, Chua AO, Mizel SB (1984) Nature (London) 312:458–62CrossRefGoogle Scholar
  4. 4.
    Demezuk S, Baumberger C, Mach B, Dayer JM (1987) J Mol Cell Immunol 255–265Google Scholar
  5. 5.
    Endres S, Cannon JG, Ghorbani R, Dempsey RA, Sisson SD, Lonnemann G, van der Meer JWM, Wolff SM, Dinarello CA (1989) Eur J Immunol 19:2327–2333PubMedCrossRefGoogle Scholar
  6. 6.
    Lonnemann G, Endres S, van der Meer JW, Cannon JG, Koch KM, Dinarello CA (1989) Eur J Immunol 19:1531–1536PubMedCrossRefGoogle Scholar
  7. 7.
    Rubartelli A, Cozzolino F, Talio M, Sitia R (1990) EMBO J 9:1503–1510PubMedGoogle Scholar
  8. 8.
    Kurt-Jones EA, Beller DI, Mizel SB, Unanue ER (1985) Proc Nad Acad Sci USA 82:1204CrossRefGoogle Scholar
  9. 9.
    Beuscher HU, Collen HR (1988) Mol Immunol 25:1189PubMedCrossRefGoogle Scholar
  10. 10.
    Brody DT, Durum SK (1989) J Immunol 143:1183PubMedGoogle Scholar
  11. 11.
    Minnich-Carruth LL, Suttles J, Mizel SB (1989) J Immunol 142:526PubMedGoogle Scholar
  12. 12.
    Bailly S, Ferrua B, Fay M, Gougerot-Pocidalo MA (1990) Eur Cytokine Net 1:47–51Google Scholar
  13. 13.
    Bendtzen K, Mandrup-Poulsen T, Nerup J, Nielsen JH, Dinarello CA, Svenson M (1986) Science 232:1545–1547PubMedCrossRefGoogle Scholar
  14. 14.
    Spinas GA, Mandrup-Poulsen T, Mlvig J, Baek L, Bendtzen K, Dinarello CA, Nerup J (1986) Acta Endocrinol (Copenh) 113:551–558Google Scholar
  15. 15.
    Fibbe WE, van da- Meer JWM, Falkenburg JHF, Hamilton MS, Kluin PM, Dinarello CA (1989) Esp. Hematol 17:805–808Google Scholar
  16. 16.
    van der Meer JW, Barza M, Wolff SM, Dinarello CA (1988) Proc Natl Acad Sci USA 85:1620–1623PubMedCrossRefGoogle Scholar
  17. 17.
    Beutler B, Krochin N, Milsark IW, Luedke C, Cerami A (1986) Science 232:977–980PubMedCrossRefGoogle Scholar
  18. 18.
    Dinarello CA (1989) Adv Immunol 44:153–205PubMedCrossRefGoogle Scholar
  19. 19.
    Dinarello CA, Cannon JG, Wolff SM (1988) Rev Infect Dis 10:168–189PubMedCrossRefGoogle Scholar
  20. 20.
    Hellerstein MK, Meydani SM, Meydani M, Wu K, Dinarello CA (1989) J Clin Invest 84:228–235PubMedCrossRefGoogle Scholar
  21. 21.
    Walter J, Davenne D, Shoham S, Dinarello CA, Krueger JM (1986) Am J Physiol 86:R96-R103Google Scholar
  22. 22.
    Raz A, Wyche A, Siegel N, Needleman P (1988) J Biol Chem 263:3022–3028PubMedGoogle Scholar
  23. 23.
    Schweizer A, Feige U, Fontana A, Muller K, Dinarello CA (1988) Agents Actions 25:246–251PubMedCrossRefGoogle Scholar
  24. 24.
    Cominelli F, Nast CC, Dinarello CA, Gentilini P, Zipser RD (1989) Gastroenterology 97:1400–1405PubMedGoogle Scholar
  25. 25.
    Dejana E, Breviario F, Erroi A, Bussolino F, Mussoni L, Gramse M, Pintucci G, Casali B, Dinarello CA, Van Damme J, Mantovani A (1987) Blood 69:695–9PubMedGoogle Scholar
  26. 26.
    Okusawa S, Gelfand JA, Ikejima T, Connolly RJ, Dinarello CA (1988) J Clin Invest 81:1162–1172PubMedCrossRefGoogle Scholar
  27. 27.
    Dayer JM, de Rochemonteix B, Burrus B, Demezuk S, Dinarello CA (1986) J Clin Invest 77:645–648PubMedCrossRefGoogle Scholar
  28. 28.
    Schnyder J, Payne T, Dinarello CA (1987) J Immunol 138:496–503PubMedGoogle Scholar
  29. 29.
    Ernst TJ, Ritchie AR, Demetri GD, Griffin JD (1989) J Biol Chem 264:5700–3PubMedGoogle Scholar
  30. 30.
    Griffin JD, Cannistra SA, Sullivan R, Demetri GD, Ernst TJ, Kanakura Y (1990) Int J Cell Cloning 1:35–44CrossRefGoogle Scholar
  31. 31.
    Kohase M, May LT, Tamm I, Vilcek J, Sehgai PB (1987) Mol Cell Biol 7:273–280PubMedGoogle Scholar
  32. 32.
    Gershenwald JE, Fong Y, Fahey TJI, Calvano SE, Chizzonite R, Kilian PL, Lowry SF, Moldawer LL (1990) Proc Natl Acad Sci USA 87:4966–4970PubMedCrossRefGoogle Scholar
  33. 33.
    Fenton MJ, Clark BD, Collins KL, Webb AC, Rich A, Auron PE (1987) J Immunol 138:3972–3979PubMedGoogle Scholar
  34. 34.
    Schindler R, Clark BD, Dinarello CA (1990) J Biol Chem 265:10232–10237PubMedGoogle Scholar
  35. 35.
    Schindler R, Ghezzi P, Dinarello CA (1990) J Immunol 144:2216–2222PubMedGoogle Scholar
  36. 36.
    Knudsen PJ, Dinarello CA, Strom TB (1987) J Immunol 139:4129–4134PubMedGoogle Scholar
  37. 37.
    Ucla C, Roux-Lombard P, Fey S, Dayer JM, Mach B (1990) J Clin Invest 85:185–191PubMedCrossRefGoogle Scholar
  38. 38.
    Warner SJC, Auger KR, Libby P (1987) J Exp Med 165:1316–1331PubMedCrossRefGoogle Scholar
  39. 39.
    Warner SJC, Auger KR, Libby P (1987) J Immunol 139:1911–1917PubMedGoogle Scholar
  40. 40.
    Ruschen S, Lemm G, Warnatz H (1989) Clin Exp. Immunol 76:246PubMedGoogle Scholar
  41. 41.
    Schade UF, Burmeister I, Engel R (1987) Biochem Biophys Res Comm 147:695–700PubMedCrossRefGoogle Scholar
  42. 42.
    Lee TH, Hoover RL, Williams ID et al. (1985) N Engl J Med 312:1217–1224PubMedCrossRefGoogle Scholar
  43. 43.
    Payan DG, Wong MY, Chemov-Rogan T et al. (1986) J Clin Immunol 6:402–410PubMedCrossRefGoogle Scholar
  44. 44.
    Endres S, Ghorbani R, Kelley YE, Georgilis K, Lonnemann G, van der Meer JW, Cannon JG, Rogers TS, Klempner MS, Weber PC, Wolff SM, Dinarello CA (1989) N Engl J Med 320:265–271PubMedCrossRefGoogle Scholar
  45. 45.
    Meydani SN, Endres S, Woods MM, Goldin BR, Soo C, Morrill-Labrode A, Dinarello CA, Gorbach SL (1990) J Nutr (in press)Google Scholar
  46. 46.
    Kremer JM, Lawrence DA, Jubiz W, DiGiacomo R, Rynes R, Bartholomew LE, Sherman M (1990) Arthritis Rheum 33:810–820PubMedCrossRefGoogle Scholar
  47. 47.
    Knudsen PJ, Dinarello CA, Strom TB (1986) JImmunol 137:3189–3194Google Scholar
  48. 48.
    Streiter RM, Remick PA, Ward PA, Spengler RN; Lynch JP, Larrick J, Kunkel SL (1988) Biochem Biophys Res Comm 155:1230–1236CrossRefGoogle Scholar
  49. 49.
    Vannier E, Miller LC, Schindler R, Terlain B, Dinarello CA (1989) Cytokine 1:123Google Scholar
  50. 50.
    Bomsztyk K, Sims JE, Stanton TH, Slack J, McMahan CJ, Valentine MA, Dower SK (1989) Proc Natl Acad Sci USA 86:8034–8038PubMedCrossRefGoogle Scholar
  51. 51.
    Chizzonite R, Traitt T, Kilian PL, Stern AS, Nunes P, Parker KP, Kaffka KL, Chua AO, Lugg DK, Gluber U (1989) Proc Natl Acad Sci USA 86:8029–8033PubMedCrossRefGoogle Scholar
  52. 52.
    Savage N, Puren AJ, Orencole SF, Ikejima T, Clark BD, Dinarello CA (1989) Cytokine 1:23–25PubMedCrossRefGoogle Scholar
  53. 53.
    Rosoff PM, Savage N, Dinarello CA (1988) Cell 54:73–81PubMedCrossRefGoogle Scholar
  54. 54.
    Seckinger P, Dayer JM (1987) Ann Inst Pasteur/immunol 138:461–516CrossRefGoogle Scholar
  55. 55.
    Seckinger P, Lowenthal JW, Williamson K, Dayer JM, MacDonald HR (1987) J Immunol 139:1546–1549PubMedGoogle Scholar
  56. 56.
    Liao Z, Grimshaw RS, Rosenstreich DL (1984) J Exp Med 159:125–136CrossRefGoogle Scholar
  57. 57.
    Dinarello CA, Rosenwasser U, Wolff SM (1981) J Immunol 127:2517–2519PubMedGoogle Scholar
  58. 58.
    Balavoine JF, de RB, Williamson K, Seckinger P, Cruchaud A, Dayer JM (1986) J Clin Invest 78:1120–1124PubMedCrossRefGoogle Scholar
  59. 59.
    Engelmann H, Aderka D, Rubinstein M, Rotman D, Wallach D (1989) J Biol Chem 264:11974–11980PubMedGoogle Scholar
  60. 60.
    Arend WP, Joslin FG, Thompson RC, Hannum CH (1989) J Immunol 143:1851–1858PubMedGoogle Scholar
  61. 61.
    Eisenberg SP, Evans RJ, Arend WP, Verderber E, Brewer MT, Hannum CH, Thompson RC (1990) Nature (London) 343:341–346CrossRefGoogle Scholar
  62. 62.
    Seckinger P, Klein-Nulend J, Alander C, Thompson RC, Dayer JM, Raisz LG (1990) J Immunol 145:4181–4184PubMedGoogle Scholar
  63. 63.
    Ohlsson K, Bjork P, Bergenfeldt M, Eisenberg SP, Childs J, Hannum CH, Thompson RC (1989) Cytokine 1:131aGoogle Scholar
  64. 64.
    Fong Y, Tracey KJ, Moldawer LL, Hesse DG, Manogue KB, Kenney JS, Lee AT, Kuo GC, Allison AC, Lowry SF, Cerami A (1989) J Exp Med 170:1627–1633PubMedCrossRefGoogle Scholar
  65. 65.
    Ohlsson K, Bjork P, Bergenfeldt M, Hageman R, Thompson RC (1990) Nature (London) 348:550–552CrossRefGoogle Scholar
  66. 66.
    Wakabayashi G, Gelfand JA, Burke JF, Thompson RC, Dinarello CA (1991) FASEB J 5:338–343PubMedGoogle Scholar
  67. 67.
    Cominelli F, Nast CC, Llerena R, Dinarello CA, Zipser RD (1990) J Clin Invest 85:582–586PubMedCrossRefGoogle Scholar
  68. 68.
    Cominelli F, Nast CC, Clark BD, Schindler R, Llerena R, Eysselein VE, Thompson RC, Dinarello CE (1990) J Clin Invest 86:972–980PubMedCrossRefGoogle Scholar
  69. 69.
    Cominelli F, Llerena F, Clark BD, Nast CC, Thompson RC, Dinarello CA (1990) Lymph Res 9:597Google Scholar
  70. 70.
    Bagby GCJ, Dinarello CA, Wallace P, Wagner C, Hefeneider S, McCall E (1986) J Clin Invest 78:1316–1323PubMedCrossRefGoogle Scholar
  71. 71.
    Cozzolino F, Rubartelli A, Aldinucci D, Sitia R, Torcia M, Shaw A, Di Guglielmo R (1989) Proc Natl Acad Sci USA 86:2369–2373PubMedCrossRefGoogle Scholar
  72. 72.
    Ernst TJ, Ritchie AR, Demetri GD, Griffin JD (1989) J Biol Chem 264:5700–3PubMedGoogle Scholar
  73. 73.
    Zucali JR, Dinarello CA, Obion DJ, Gross MA, Anderson L, Weiner RS (1986) J Clin Invest 77:1857–1863PubMedCrossRefGoogle Scholar
  74. 74.
    Bagby GCJ, Dinarello CA, Neerhout RC, Ridgway D, McCall E (1988) J Clin Invest 82:1430–1436PubMedCrossRefGoogle Scholar
  75. 75.
    Rambaldi A, Torcia M, Bettoni S, Barbui T, Vannier E, Dinarello CA, Cozzolino F (1990) Blood 76:114aGoogle Scholar
  76. 76.
    Mclntrye KW, Stepan GJ, Kolinsky KD, Benjamin WR, Plocinski JM, Kaffka KL, Campen CA, Chizzonite RA, Kilian PL (1991) J Exp Med 173:931–939CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1991

Authors and Affiliations

  • C. A. Dinarello
    • 1
  1. 1.Department of MedicineTufts University School of Medicine and New England Medical CenterBostonUSA

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