Original communication| Volume 109, ISSUE 6, P698-705, June 1991

Tumor necrosis factor and interleukin-1 protection against the lethal effects of tumor necrosis factor

  • Brett C. Sheppard
    Surgical Metabolism Section, Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Md., USA
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  • Jeffrey A. Norton
    Reprint requests: Jeffrey A. Norton, MD, Head, Surgical Metabolism Section, Surgery Branch, National Cancer Institute/NIH, Building 10, Room 2B07, Bethesda, MD 20892.
    Surgical Metabolism Section, Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Md., USA
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  • Author Footnotes
    ∗ Current address: Oregon Health Sciences University, Department of Surgery, 3181 SW San Jackson Park Road, Portland, OR 92201.
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      Based on the hypothesis that tumor necrosis factor (TNF) causes the lethality of gram-negative sepsis and previous work of tolerance to the lethal effects of TNF induced by repetitive exposure to sublethal intraperitoneal doses of human recombinant (r) TNF, we studied the protective role of a single sublethal intravenous dose of either rTNF (100 μg/kg) or recombinant interleukin-1 (rIL-1; 105 units/kg) or both before a subsequent lethal intravenous dose of rTNF (800 to 1000 μg/kg) in Math Eq mice. Mice were treated with a single intravenous dose of saline, rTNF, rIL-1 or both cytokines and challenged within 2 hours to 10 days with a lethal dose of rTNF. Mice treated with rTNF showed significant protection against the lethal effects of TNF when the treatment dose was given only 2 hours before the lethal dose, but maximal protection required a 24-hour interval and lasted as long as 8 days. The treatment dose of rTNF was toxic, and it resulted in occasional treatment deaths. Mice treated with rIL-1 showed maximal protection when treatment was given only 2 hours before challenge and protection lasted for 8 days. No toxicity was apparent secondary to IL-1 treatment. The combination of rIL-1 and rTNF was not as effective as either cytokine alone. The results suggest that rTNF or rIL-1 may be clinically useful in the prevention and treatment of sepsis lethality by the induction of tolerance to the lethal effects of TNF. The more promising cytokine appears to be rIL-1 because it has less toxicity and more rapid induction of full therapeutic effectiveness.
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