Journal of Clinical Immunology

, Volume 8, Issue 6, pp 426–436 | Cite as

Induction of circulating tumor necrosis factor (TNFα) as the mechanism for the febrile response to interleukin-2 (IL-2) in cancer patients

  • James W. Mier
  • Gloria Vachino
  • Jos W. M. van der Meer
  • Robert P. Numerof
  • Sharlene Adams
  • Joseph G. Cannon
  • Harry A. Bernheim
  • Michael B. Atkins
  • David R. Parkinson
  • Charles A. Dinarello
Original Articles


Fever is frequently observed in cancer patients treated with high-dose recombinant human interleukin-2 (rIL-2). The preincubation of rIL-2 with polymyxin B, an antibiotic that inhibits the biologic effects of endotoxins, did not diminish the pyrogenicity of IL-2 in New Zealand rabbits, indicating that IL-2-induced fever is not due to contaminating endotoxins. In contrast to interleukin-1 (IL-1), tumor necrosis factor (TNF), and interferon α, which cause fever through their effects on arachidonic acid metabolism in the hypothalamus, IL-2 was unable to induce prostaglandin E2 synthesis in hypothalamic cells or fibroblastsin vitro, suggesting that IL-2 is not intrinsically pyrogenic. To determine if IL-2-induced fever is mediated indirectly through the generation of pyrogenic cytokines, culture supernatants from IL-2-stimulated human peripheral blood mononuclear cells were screened for the presence of pyrogens by direct injection into rabbits and by measuring the amounts of IL-1α, IL-1β, and TNFα by specific radioimmunoassays (RIA). All three cytokines were readily detected by RIA in these supernatants, which in turn caused fever when injected into rabbits. Furthermore, in six of six cancer patients treated with rIL-2, elevated levels of TNFα were detected in the plasma by RIA 2 hr after IL-2 administration. Plasma TNF levels increased from pretreatment values of 14±7 to 765±150 pg/ml 2 hr after an IL-2 injection. These results strongly implicate IL-2-induced pyrogenic cytokines, in particular TNFα, as a major cause of the fever and possibly other aspects of the acute-phase response associated with IL-2 therapy.

Key words

Interleukin-2 tumor necrosis factor fever 


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  1. 1.
    Lotze M, Matory Y, Ettinghausen S, Raynor A, Sharrow S, Siepp C, Custer M, Rosenberg S:In vivo administration of purified human Interleukin-2. II. Half-life, immunologic effects, and expansion of peripheral lymphoid cellsin vivo with recombinant IL-2. J Immunol 135:2865–2870, 1985Google Scholar
  2. 2.
    Atkins MB, Gould JA, Allegretta M, Li JJ, Dempsey RA, Rudders RA, Parkinson DR, Reichlin S, Mier JW: Phase I evaluation of recombinant interleukin-2 in patients with advanced malignant disease. J Clin Oncol 4:1380–1391, 1986Google Scholar
  3. 3.
    Rosenberg SA, Lotze MT, Muul LM, Leitman S, Chang AE, Ettinghausen SE, Matory YL, Skibber JM, Shiloni E, Vetto JT, Siepp CA, Simpson C, Reichart CM: Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 313:1485–1492, 1985Google Scholar
  4. 4.
    Rosenberg SA, Lotze MT, Muul LM, Chang AE, Avis FP, Leitman S, Linehan WM, Robertson CN, Lee RE, Rubin JT, Seipp CA, Simpson CG, White DE: A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 316:889–897, 1987Google Scholar
  5. 5.
    West WH, Tauer KW, Yannelli JR, Marshall GD, Orr DW, Thurman GB, Oldham RK: Constant infusion recombinant interleukin-2 in adoptive immunotherapy of advanced cancer. N Engl J Med 316:898–905, 1987Google Scholar
  6. 6.
    Mier JW, Dinarello CA, Atkins MB, Punsal PI, Perlmutter DH: Regulation of hepatic acute phase protein synthesis by products of interleukin-2 (IL-2)-stimulated human peripheral blood mononuclear cells. J Immunol 139:1268–1272, 1987Google Scholar
  7. 7.
    Handa K, Suzuki R, Matsui H, Shimizu Y, Kumagai K: Natural killer (NK) cells as a responder to interleukin-2 (IL-2). II. IL-2-induced interferon-gamma production. J Immunol 130:988–993, 1983Google Scholar
  8. 8.
    Nedwin GE, Svedersky LP, Bringman TS, Palladino MA, Goeddel DV: Effect of interleukin-2, interferon-gamma, and mitogens on the production of tumor necrosis factor alpha and beta. J Immunol 135:2492–2497, 1985Google Scholar
  9. 9.
    Dinarello CA, Cannon JG, Wolff SM, Bernheim HA, Beutler B, Cerami A, Figari IS, Palladino MA, O'Connor JV: Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin-1. J Exp Med 163:1433–1450, 1986Google Scholar
  10. 10.
    Chapman PB, Lester TJ, Casper ES, Gabrilove JL, Wong GY, Kempin SJ, Gold PJ, Welt S, Warren RS, Starnes HF, Sherwin SA, Old LJ, Oettgen HF: Clinical pharmacology of recombinant human tumor necrosis factor in patients with advanced cancer. J Clin Oncol 5:1942–1951, 1987Google Scholar
  11. 11.
    Gillis S, Ferm M, Ou W, Smith K: T-cell growth factor: Parameters of production and a quantitative microassay for activity. J Immunol 120:2027–2032, 1978Google Scholar
  12. 12.
    Dinarello CA, Bernheim HA, Cannon JG, LoPreste G, Warner SJC, Webb AC, Auron PE: Purified35S-met,3H-Leu-labeled human monocyte interleukin-1 with endogenous pyrogen activity. Br J Rheumatol 24:59–64, 1985Google Scholar
  13. 13.
    Dinarello CA: Endogenous pyrogen.In Methods for Studying Mononuclear Phagocytes, D Adams, P Edelson, H Koren (eds). New York, Academic Press, 1981, pp 629–639Google Scholar
  14. 14.
    Duff GW, Atkins E: The inhibiting effect of polymyxin B on endotoxin-induced endogenous pyrogen production. J Immunol Methods 52:333–340, 1982Google Scholar
  15. 15.
    Dinarello CA, Bernheim HA: Ability of leukocytic pyrogen to stimulate brain prostaglandinin vitro. J Neurochem 37:702–708, 1981Google Scholar
  16. 16.
    Van der Meer JWM, Endres S, Lonneman G, Cannon JG, Ikejima T, Okusawa S, Gelfand JA, Dinarello CA: Concentrations of immunoreactive human tumor necrosis factor alpha produced by human mononuclear cellsin vitro. J Leuk Biol 43:216–223, 1988Google Scholar
  17. 17.
    Lonneman G, Endres S, Van der Meer JWM, Cannon JG, Dinarello CA: A radioimmunoassay for interleukin-1 alpha: Measurement of IL-1 alpha produced in vitro by human blood mononuclear cells stimulated with endotoxin. Lymphokine Res (in press)Google Scholar
  18. 18.
    Lisi PJ, Chu CW, Koch GA, Endres S, Lonneman G, Dinarello CA: Development and use of a radioimmunoassay for human interleukin-1 beta. Lymphokine Res 6:229–244, 1987Google Scholar
  19. 19.
    Cannon JD, Dinarello CA: Increased plasma interleukin-1 activity in women after ovulation. Science 227:1247–1249, 1985Google Scholar
  20. 20.
    Orencole SF, Ikejima T, Cannon JG, Lonnemann G, Saijo T, Dinarello CA: A subclone of D10.G4.1 T-cells which specifically proliferates in response to interleukin-1 at attograms/ml in the absence of mitogen. Lymphokine Res 6:1210a (abstr), 1987Google Scholar
  21. 21.
    Mier JW, Souza L, Allegretta M, Boone T, Bernheim HA, Dinarello CA: Dissimilarities between purified human interleukin-1 and recombinant interleukin-2 in the induction of fever, brain prostaglandin and acute phase protein synthesis. J Biol Response Modifiers 4:35–45, 1985Google Scholar
  22. 22.
    Kupper T, Horowitz M, Lee F, Robb R, Flood PM: Autocrine growth of T-cells independent of interleukin-2: Identification of interleukin-4 (IL-4, BSF-1) as an autocrine growth factor for a cloned antigen-specific helper T cell. J Immunol 138:4280–4287, 1987Google Scholar
  23. 23.
    Dinarello CA, Rosenwasser LJ, Wolff SM: Demonstration of a circulatory suppressor factor of thymocyte proliferation during endotoxin fever in humans. J Immunol 127:2519–2523, 1981Google Scholar
  24. 24.
    Duff GW, Atkins E: The detection of endotoxin byin vitro production of endogenous pyrogen: Comparison with limulus amebocyte lysate gelation. J Immunol Methods 52:323–331, 1982Google Scholar
  25. 25.
    Dinarello CA, O'Connor JV, LoPreste G, Swift RL: Human leukocyte pyrogen test to detect pyrogenic material in growth hormone from recombinantE. coli. J Clin Micro 20:323–329, 1984Google Scholar
  26. 26.
    Dinarello CA, Cannon JC, Mier JW, Bernheim HA, LoPreste G, Lynn DL, Love RN, Webb AC, Auron PE, Reuben RC, Rich A, Wolff SM, Putney SD: Multiple biological activities of human recombinant interleukin-1. J Clin Invest 77:1734–1739, 1986Google Scholar
  27. 27.
    Dinarello CA, Bernheim HA, Duff GW, Le HV, Nagabhushan TL, Hamilton TC, Coceani F: Mechanism of fever induced by recombinant human interferon. J Clin Invest 74:906–913, 1984Google Scholar
  28. 28.
    Svedersky L, Nedwin G, Goeddel D, Palladino M: Interferon gamma enhances induction of lymphotoxin in recombinant interleukin-2-stimulated peripheral blood mononuclear cells. J Immunol 134:1604–1608, 1985Google Scholar
  29. 29.
    Cannon JG, Evans WJ, Hughes VA, Meredith CN, Dinarello CA: Physiologic mechanisms contributing to increased interleukin-1 secretion. J Appl Physiol 61(5):1869–1874, 1986Google Scholar
  30. 30.
    Takacs L, Smith M, Kovacs E, Young H, Durum S: Expression of IL-1 alpha and beta genesin vivo as analyzed byin situ hybridization histochemistry. J Leuk Biol 42(5):581 (abstr 123), 1987Google Scholar
  31. 31.
    Numerof RP, Aronson FR, Mier JW: Interleukin-2 stimulates the production of interleukin-1 alpha and interleukin-1 beta by human peripheral blood mononuclear cells. J Immunol (in press)Google Scholar
  32. 32.
    Ostensen ME, Thiele DL, Lipsky PE: Tumor necrosis factor-α enhances cytolytic activity of human natural killer cells. J Immunol 138:4185–4191, 1987Google Scholar
  33. 33.
    Bevilacqua MP, Pober JS, Wheeler ME, Mendrick D, Cotran RS, Gimbrone MA Jr: Interleukin-1 acts on cultured human vascular endothelial cells to increase the adhesion of polymorphonuclear leukocytes, monocytes and related leukocyte cell lines. J Clin Invest 76:2003–2012, 1985Google Scholar

Copyright information

© Plenum Publishing Corporation 1988

Authors and Affiliations

  • James W. Mier
    • 1
    • 2
  • Gloria Vachino
    • 1
  • Jos W. M. van der Meer
    • 3
  • Robert P. Numerof
    • 1
    • 2
  • Sharlene Adams
    • 2
  • Joseph G. Cannon
    • 3
  • Harry A. Bernheim
    • 4
  • Michael B. Atkins
    • 1
  • David R. Parkinson
    • 1
  • Charles A. Dinarello
    • 3
  1. 1.Division of Hematology-Oncology, Department of MedicineTufts University School of Medicine and New England Medical CenterBoston
  2. 2.Immunology ProgramTufts University School of MedicineBoston
  3. 3.Division of Infectious Disease, Department of MedicineTufts University School of Medicine and New England Medical CenterBoston
  4. 4.Department of BiologyTufts UniversityMedford

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