Endogenous Mechanisms Regulating TNF and IL-1 during Sepsis

  • T. van der Poll
  • S. F. Lowry
Part of the Yearbook of Intensive Care and Emergency Medicine book series (YEARBOOK, volume 1995)


In the past decade, it has become increasingly clear that proinflammatory cytokines play a prominent role in the pathophysiology of sepsis. Of these, tumor necrosis factor α (TNF-α) and interleukin 1 (IL-1) seem to be of particular importance. Administration of either TNF-α or IL-1 to experimental animals results in a syndrome that mimics sepsis, and therapy specifically directed against either cytokine protects against lethality in experimental sepsis and endotoxe- mia. In recent years, several endogenous mechanisms meant to protect the host against excessive activity of these highly potent cytokines have been identified. In this chapter, we will briefly discuss current knowledge of the roles of TNF and IL-1 in the pathogenesis of sepsis, and will provide an overview of endogenous mechanisms, that regulate the production and activities of TNF and IL-1.


Endogenous Mechanism Tumor Necrosis Factor Level Experimental Endotoxemia Tumor Necrosis Factor Activity Tumor Necrosis Factor Receptor Type 
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  1. 1.
    Van der Poll T, Lowry SF (1995) Tumor necrosis factor in sepsis: Mediator of multiple organ failure or essential part of host defense? Shock (in press)Google Scholar
  2. 2.
    Dinarello CA (1991) Interleukin-1 and interleukin-1 antagonism. Blood 77: 1627–1652PubMedGoogle Scholar
  3. 3.
    Tartaglia LA, Goeddel DV (1992) Two TNF receptors. Immunol Today 13: 151–153PubMedCrossRefGoogle Scholar
  4. 4.
    Sims JE, Giri JG, Dower SK (1994) The two interleukin-1 receptors play different roles in IL-1 actions. Clin Immunol Immunopathol 72: 9–14PubMedCrossRefGoogle Scholar
  5. 5.
    Waage A, Halstensen A, Espevik T (1987) Association between tumour necrosis factor in serum and fatal outcome in patients with meningococcal disease. Lancet 1: 355–357PubMedCrossRefGoogle Scholar
  6. 6.
    Girardin E, Grau GE, Dayer JM, and the J5 Study Group (1988) Tumor necrosis factor and interleukin-1 in the serum of children with severe infectious purpura. N Engl J Med 319: 397–400PubMedCrossRefGoogle Scholar
  7. 7.
    Lowry SF, Calvano SE, van der Poll T (1995) Measurement of inflammatory mediators in clinical sepsis. In: Sibbald WJ, Vincent JL (eds) Clinical Trials for the Treatment of Sepsis. Springer-Verlag, Heidelberg, Vol 19, pp 86–105CrossRefGoogle Scholar
  8. 8.
    Hesse DG, Tracey KJ, Fong Y, et al (1988) Cytokine appearance in human endotoxemia and primate bacteremia. Surg Gynecol Obstet 166: 147–153PubMedGoogle Scholar
  9. 9.
    Fong Y, Marano MA, Moldawer LL, et al (1990) The acute splanchnic and peripheral tissue metabolic response to endotoxin in humans. J Clin Invest 85: 1896–1904PubMedCrossRefGoogle Scholar
  10. 10.
    Fong Y, Tracey KJ, Moldawer LL, et al (1989) Antibodies to cachectin/tumor necrosis factor reduce interleukin-1β and interleukin-6 appearance during lethal bacteremia. J Exp Med 170: 1627–1633PubMedCrossRefGoogle Scholar
  11. 11.
    Tracey KJ, Lowry SF, Fahey III TJ, et al (1987) Cachectin/tumor necrosis factor induces lethal shock and stress hormone responses in the dog. Surg Gynecol Obstet 164: 415–422PubMedGoogle Scholar
  12. 12.
    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
  13. 13.
    Van der Poll T, Büller HR, ten Cate H, et al (1990) Activation of coagulation after administration of tumor necrosis factor to normal subjects. N Engl J Med 322: 1622–1627PubMedCrossRefGoogle Scholar
  14. 14.
    Van der Poll T, Levi M, Büller HR, et al (1991) Fibrinolytic response to tumor necrosis factor in healthy subjects. J Exp Med 174: 729–732PubMedCrossRefGoogle Scholar
  15. 15.
    Van der Poll T, van Deventer SJH, Hack CE, et al (1992) Effects on leukocytes following injection of tumor necrosis factor into healthy humans. Blood 79: 693–698PubMedGoogle Scholar
  16. 16.
    Van der Poll T, Romijn JA, Endert E, Borm JJ, Büller HR, Sauerwein HP (1991) Tumor necrosis factor mimics the metabolic response to acute infection in healthy humans. Am J Physiol 261: E457–E465PubMedGoogle Scholar
  17. 17.
    Echtenacher B, Falk W, Mannel DN, et al (1990) Requirement of endogenous tumor necrosis factor/cachectin for recovery from experimental peritonitis. J Immunol 145: 3762–3766PubMedGoogle Scholar
  18. 18.
    Zanetti G, Heumann D, Gérain J, et al (1992) Cytokine production after intravenous or peritoneal gram-negative bacterial challenge in mice. Comparative protective efficacy of antibodies to tumor necrosis factor-α and to lipopolysaccharide. J Immunol 148: 1890–1897PubMedGoogle Scholar
  19. 19.
    Ohlsson K, Björk P, Bergenfeldt M, Hageman R, Thompson RC (1990) Interleukin-1 receptor antagonist reduces mortality from endotoxic shock. Nature 348: 550–552PubMedCrossRefGoogle Scholar
  20. 20.
    Fischer E, Marano MA, van Zee KJ, et al (1992) Interleukin-1 receptor blockade improves survival and hemodynamic performance in Escherichia coli septic shock, but fails to alter host responses to sublethal endotoxemia. J Clin Invest 89: 1551–1557PubMedCrossRefGoogle Scholar
  21. 21.
    Aiura K, Gelfand JA, Wakabayashi G, et al (1991) Interleukin-1 receptor antagonist blocks staphylococcal-induced shock in rabbits. Cytokine 3: 498–507Google Scholar
  22. 22.
    Fisher Jr CJ, Dhainaut JFA, Opal SM, et al (1994) Recombinant human interleukin-1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. JAMA 271: 1836–1840PubMedCrossRefGoogle Scholar
  23. 23.
    Moore KW, O’Garra A, de Waal-Malefyt R, Vieira P, Mosmann TR (1993) Interleukin 10. Ann Rev Immunol 11: 165–190CrossRefGoogle Scholar
  24. 24.
    Marchant A, Devière J, Byl B, de Groote D, Vincent JL, Goldman M (1994) Interleukin- 10 production during septicaemia. Lancet 343: 707–708PubMedCrossRefGoogle Scholar
  25. 25.
    Van der Poll T, Jansen J, Levi M, ten Cate H, ten Cate JW, van Deventer SJH (1995) Regulation of interleukin-10 release by tumor necrosis factor in humans and chimpanzees. J Exp Med (in press)Google Scholar
  26. 26.
    Marchant A, Bruyns C, Vandenabeele P, et al (1994) IL-10 controls IFN-γ and TNF production during experimental endotoxemia. Eur J Immunol 24: 1167–1171PubMedCrossRefGoogle Scholar
  27. 27.
    Van der Poll T, Marchant A, Berman L, et al (1995) Endogenous interleukin-10 protects against death in septic peritonitis in mice. Surg Forum (in press)Google Scholar
  28. 28.
    Gérard C, Bruyns C, Marchant A, et al (1993) Interleukin-10 reduces the release of tumor necrosis factor and prevents lethality in experimental endotoxemia. J Exp Med 177: 547–550PubMedCrossRefGoogle Scholar
  29. 29.
    Leeuwenberg JFM, Jeunhomme TMAA, Buurman WA (1994) Slow release of soluble TNF receptors by monocytes in vitro. J Immunol 152: 4036–4040PubMedGoogle Scholar
  30. 30.
    Schindler R, Mancilla J, Endres S, Ghorbani R, Clark R, Dinarello CA (1990) Correlations and interactions in the production of interleukin-6 (IL-6), IL-1, and tumor necrosis factor (TNF) in human blood mononuclear cells: IL-6 suppresses IL-1 and TNF. Blood 75: 40–47PubMedGoogle Scholar
  31. 31.
    Tilg H, Trehu E, Atkins MB, Dinarello CA, Mier JW (1994) Interleukin-6 (IL-6) as an antiinflammatory cytokine: Induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55. Blood 83: 113–118PubMedGoogle Scholar
  32. 32.
    Libert C, Vink A, Coulie P, et al (1992) Limited involvement of interleukin-6 in the pathogenesis of lethal septic shock as revealed by the effect of monoclonal antibodies against interleukin-6 or its receptor in various murine models. Eur J Immunol 22: 2625–2630PubMedCrossRefGoogle Scholar
  33. 33.
    Van der Poll T, Levi M, Hack CE, et al (1994) Elimination of interleukin-6 attenuates coagulation activation in experimental endotoxemia in chimpanzees. J Exp Med 179: 1253–1259PubMedCrossRefGoogle Scholar
  34. 34.
    Santos AA, Scheltinga MR, Lynch E, et al (1993) Elaboration of interleukin-1 receptor antagonist is not attenuated by glucocorticoids after endotoxemia. Arch Surg 128: 138–144PubMedCrossRefGoogle Scholar
  35. 35.
    Barber AE, Coyle SM, Marano MA, et al (1993) Glucocorticoid therapy alters hormonal and cytokine responses to endotoxin in man. J Immunol 150: 1999–2006PubMedGoogle Scholar
  36. 36.
    Severn A, Rapson NT, Hunter CA, Liew FY (1992) Regulation of tumor necrosis factor production by adrenaline and β-adrenergic agonists. J Immunol 148: 3441–3445PubMedGoogle Scholar
  37. 37.
    Van der Poll T, Jansen J, Endert E, Sauerwein HP, van Deventer SJH (1994) Noradrenaline inhibits lipopolysaccharide-induced tumor necrosis factor and interleukin-6 production in human whole blood. Infect Immunol 62: 2046–2050Google Scholar
  38. 38.
    Monastra G, Secchi EF (1993) β-adrenergic receptors mediate in vivo the adrenaline inhibition of lipopolysaccharide-induced tumor necrosis factor release. Immunol (Letters) 38: 127–130CrossRefGoogle Scholar
  39. 39.
    Satomi N, Sakurai A, Haranaka K (1985) Relationship of hypoglycemia to tumor necrosis factor production and antitumor activity: Role of glucose, insulin, and macrophages. J Nat Cancer Inst 74: 1255–1260PubMedGoogle Scholar
  40. 40.
    Fraker DL, Merino MJ, Norton JA (1989) Reversal of the toxic effects of cachectin by concurrent insulin administration. Am J Physiol 256: E725–E731PubMedGoogle Scholar
  41. 41.
    Aderka D, Engelmann H, Maor Y, Brakebusch C, Wallach D (1992) Stabilization of the bioactive of tumor necrosis factor by its soluble receptors. J Exp Med 175: 323–329PubMedCrossRefGoogle Scholar
  42. 42.
    Van Zee KJ, Kohno T, Fischer E, Rock SC, Moldawer LL, Lowry SF (1992) Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor-α in vitro and in vivo. Proc Natl Acad Sci USA 89: 4845–4849PubMedCrossRefGoogle Scholar
  43. 43.
    Jansen J, van der Poll T, Levi M, et al (1995) Inhibition of the release of soluble tumor necrosis factor receptors in experimental endotoxemia by an anti-tumor necrosis factor antibody. J Clin Immunol (in press)Google Scholar
  44. 44.
    Kuipers B, van der Poll T, Levi M, et al (1994) Platelet-activating factor antagonist TCV-309 attenuates the induction of the cytokine network in experimental endotoxemia in chimpanzees. J Immunol 152: 2438–2446PubMedGoogle Scholar
  45. 45.
    Calvano E, Thompson WA, Coyle SM, et al (1993) Changes in monocyte and soluble tumor necrosis factor (TNF) receptors during endotoxemia or sepsis. Surg Forum 44: 114–116Google Scholar
  46. 46.
    Granowitz EV, Porat R, Mier JW, et al (1992) Pharmacokinetics, safety and immunomodulatory effects of human recombinant interleukin-1 receptor antagonist in healthy humans. Cytokine 4: 353–360PubMedCrossRefGoogle Scholar
  47. 47.
    Fischer E, Van Zee KJ, Marano M, et al (1992) Interleukin-1 receptor antagonist circulates in experimental inflammation and in human disease. Blood 79: 2196–2200PubMedGoogle Scholar
  48. 48.
    Fischer E, Marano MA, Barber AE, et al (1991) Comparison between effects of interleu- kin-1α administration and sublethal endotoxemia in primates. Am J Physiol 261: R442–R448PubMedGoogle Scholar
  49. 49.
    Bargetzi MJ, Lantz M, Smith CG, et al (1993) Interleukin-1β induces interleukin-1 receptor antagonist and tumor necrosis factor binding protein in humans. Cancer Res 53: 4010–4013PubMedGoogle Scholar
  50. 50.
    Van der Poll T, van Deventer SJH, ten Cate H, Levi M, ten Cate JW (1994) Tumor necrosis factor is involved in the appearance of interleukin-1 receptor antagonist in endotoxemia. J Infect Dis 169: 665–667PubMedCrossRefGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 1995

Authors and Affiliations

  • T. van der Poll
  • S. F. Lowry

There are no affiliations available

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