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 Gerard Cannon, Harry A. Bernheim, Michael B. Atkins, David R. Parkinson, Charles A. Dinarello

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182 Scopus citations


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 fibroblasts in 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.

Original languageEnglish (US)
Pages (from-to)426-436
Number of pages11
JournalJournal of Clinical Immunology
Issue number6
StatePublished - Nov 1988


  • Interleukin-2
  • fever
  • tumor necrosis factor

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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