Interleukin-1-Induced Hypotension and the Effect of an Interleukin-1 Receptor Antagonist

  • C. A. Dinarello


The systemic effects of high doses (> 1μg/kg) of intravenously administered interleukin (IL-1) in animals include hypotension, decreased systemic vascular resistance, depressed myocardial function, lactic acidosis, leukopenia, thrombocytopenia, vascular leak, pulmonary congestion, and tissue neutrophilic infiltration with necrosis [1, 2]. The hypotensive effects of intravenously administered IL-1 in humans have been observed at doses below 1 μg/kg, and hypotension is the major clinical response limiting the maximal dose tolerated to 300 ng/kg [3]. The hypotensive effect of IL-1 may occur via various mechanisms. One mechanism appears to be due to cyclooxygenase products, and IL-1 and tumor necrosis factor (TNF) act synergistically in increasing prostaglandin E (PGE) in a variety of cells. The hypotension following an IL-1/TNF injection in rabbits is blocked by cyclooxygenase inhibitors [1]. Arterial perfusion with IL-1 increases prostanoid synthesis, which lowers the pain threshold to bradykinin [4]. TNF potentiates these effects of IL-1. IL-1 inhibits vascular smooth muscle contraction, but this is independent of prostaglandin synthesis. The inhibition of smooth muscle contraction by IL-1 appears to be due to an L-arginine-dependent increase in nitric oxide production, which leads to increased guanylate cyclase activity [5, 6].


Arthritis Leukemia Nitrite Oncol Polypeptide 


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  1. 1.
    Okusawa S, Gelfand JA, Ikejima T, Connolly RJ, Dinarello CA (1988) Interleukin 1 induces a shock-like state in rabbits. Synergism with tumor necrosis factor and the effect of cyclooxygenase inhibition. J Clin Invest 81:1162–1172PubMedCrossRefGoogle Scholar
  2. 2.
    Tredget EE, Yu YM, Zhong S, Burini R, Okusawa S, Gelfand JA, Dinarello CA, Young VR, Burke JF (1988) Role of interleukin 1 and tumor necrosis factor on energy metabolism in rabbits. Am J Physiol 255:E760–E768PubMedGoogle Scholar
  3. 3.
    Smith J, Urba W, Steis R, Janik J, Fenton B, Sharfman W, Conlon K, Sznol M, Creekmore S, Wells N, Elwood L, Keller J, Hestdal K, Ewel C, Rossio J, Kopp W, Shimuzut M, Oppenheim J, Longo D (1990) Interleukin-1 alpha: results of a phase I toxicity and immunomodulatory trial. Am Soc Clin Oncol 9:717Google Scholar
  4. 4.
    Schweizer A, Feige U, Fontana A, Muller K, Dinarello CA (1988) Interleukin-1 enhances pain reflexes. Mediation through increased prostaglandin E2 levels. Agents Actions 25:246–251PubMedCrossRefGoogle Scholar
  5. 5.
    Beasley D, Schwartz JH, Brenner BM (1991) Interleukin-1 induces prolonged L-arginine-dependent cyclic guanosine monophosphate and nitrite production in rat vascular smooth muscle cells. J Clin Invest (in press)Google Scholar
  6. 6.
    Beasley D (1990) Interleukin 1 and endotoxin activate soluble guanylate cyclase in vascular smooth muscle. Am J PhysiolGoogle Scholar
  7. 7.
    Dejana E, Breviario F, Erroi A, Bussolino F, Mussoni L, Gramse M, Pintucci G, Casali B, Dinarello CA, van Damme J, Mantovani A (1987) Modulation of endothelial cell functions by different molecular species of interleukin 1. Blood 69:695–699PubMedGoogle Scholar
  8. 8.
    Cannon JG, Tompkins RG, Gelfand JA, Michie HR, Stanford GG, van der Meer JWM, Endres S, Lonnemann G, Corsetti J, Chernow B, Wilmore DW, Wolff SM, Dinarello CA (1990) Circulating interleukin-1 and tumor necrosis factor in septic shock and experimental endotoxin fever. J Infect Dis 161:79–84PubMedCrossRefGoogle Scholar
  9. 9.
    Michie HR, Manogue KR, Spriggs DR, Revhaug A, O’Dwyer S, Dinarello CA, Cerami A, Wolff SM, Wilmore DW (1988) Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med 318:1481–1486PubMedCrossRefGoogle Scholar
  10. 10.
    Gershenwald JE, Fong YM, Fahey TJ3, Calvano SE, Chizzonite R, Kilian PL, Lowry SF, Moldawer LL (1990) Interleukin 1 receptor blockade attenuates the host inflammatory response. Proc Natl Acad Sci USA 87:4966–4970PubMedCrossRefGoogle Scholar
  11. 11.
    Wakabayashi G, Gelfand JA, Jung WK, Connolly RJ, Burke JF, Dinarello CA, (1991) Staphylococcus epidermidis induces complement activatio, TNF, IL-1, a shock-like state and tissue injury in rabbits without endotoxemia: comparison to Escherichia coli. J Clin Invest (in press)Google Scholar
  12. 12.
    Dinarello CA, Rosenwasser LJ, Wolff SM (1981) Demonstration of a circulating suppressor factor of thymocyte proliferation during endotoxin fever in humans. J Immunol 127:2517–2519PubMedGoogle Scholar
  13. 13.
    Liao Z, Grimshaw RS, Rosenstreich DL (1984) Identification of a specific interleukin-1 inhibitor in the urine of febrile patients. J Exp Med 159:125–136CrossRefGoogle Scholar
  14. 14.
    Arend WP, Joslin FG, Thompson RC, Hannum CH (1989) An IL-1 inhibitor from human monocytes. Production and characterization of biologic properties. J Immunol 143:1851–1858PubMedGoogle Scholar
  15. 15.
    Seckinger P, Dayer JM (1987) Interleukin-1 inhibitors. Ann Inst Pasteur Immunol 138:461–516CrossRefGoogle Scholar
  16. 16.
    Barak V, Treves AJ, Yanai P, Halperin M, Wasserman D, Biran S, Braun S (1986) Interleukin-1 inhibitory activity secreted by a human myelomonocytic cell line (M20). Eur J Immunol 16:1449–1452PubMedCrossRefGoogle Scholar
  17. 17.
    Seckinger P, Lowenthal JW, Williamson K, Dayer JM, MacDonald HR (1987) A urine inhibitor of interleukin-1 activity that blocks ligand binding. J Immunol 139:1546–1549PubMedGoogle Scholar
  18. 18.
    Mazzei GJ, Seckinger PL, Dayer JM, Shaw AR (1990) Purification and characterization of a 26-kDa competitive inhibitor of interleukin 1. Eur J Immunol 20:683–689PubMedCrossRefGoogle Scholar
  19. 19.
    De Balavoine JF RB, Williamson K, Seckinger P, Cruchaud A, Dayer JM (1986) Prostaglandin E2 and collagenase production by fibroblasts and synovial cells is regulated by urine-derived human interleukin 1 and inhibitor(s). J Clin Invest 78:1120–1124PubMedCrossRefGoogle Scholar
  20. 20.
    Hannum CH, Wilcox CJ, Arend WP, Joslin FG, Dripps DJ, Heimdal PL, Armes LG, Sommer A, Eisenberg SP, Thompson RC (1990) Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature 343:336–340PubMedCrossRefGoogle Scholar
  21. 21.
    Eisenberg SP, Evans RJ, Arend WP, Verderber E, Brewer MT, Hannum CH, Thompson RC (1990) Primary structure and functional expression from complementary DNA of a human interleukin-1 receptor antagonist. Nature 343:341–346PubMedCrossRefGoogle Scholar
  22. 22.
    Granowitz EV, Mancilla BD, Clark BD, Dinarello CA (1991) The IL-1 receptor antagonist blocks IL-1 binding to the IL-1RtII on human neutrophils and B-cells. Clin Res (in press)Google Scholar
  23. 23.
    Rambaldi A, Torcia M, Bettoni S, Barbui T, Vannier E, Dinarello CA, Cozzolino F (1990) Modulation of cell proliferation and cytokine production in acute myeloblastic leukemia by interleukin-1 receptor antagonist and lack of its expression by leukemic cells. Blood 76:114aGoogle Scholar
  24. 24.
    Ohlsson K, Bjork P, Bergenfeldt M, Hageman R, Thompson RC (1990) Interleukin-1 receptor antagonist reduces mortality from endotoxin shock. Nature 348:550–552PubMedCrossRefGoogle Scholar
  25. 25.
    Wakabayashi G, Gelfand JA, Burke JF, Thompson RC, Dinarello CA (1991) A specific receptor antagonist for interleukin-1 prevents E. coli-induced shock. FASEB J (in press)Google Scholar
  26. 26.
    Mancilla J, Garcia P, Dinarello CA (1991) Either interleukin-1 or the interleukin-1 receptor antagonist prevent lethal sepsis in newborn rats. Clin Res (in press)Google Scholar
  27. 27.
    Cominelli F, Nast CC, Clark BD, Schindler R, Llerena R, Eysselein VE, Thompson RC, Dinarello CA (1990) Interleukin-1 gene expression, synthesis and effect of specific IL-1 receptor blockade in rabbit immune complex colitis. J Clin Invest 86:972–980PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag, Berlin Heidelberg 1993

Authors and Affiliations

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

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