Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1

C. A. Dinarello, J. G. Cannon, S. M. Wolff, H. A. Bernheim, B. Beutler, A. Cerami, I. S. Figari, M. A. Palladino, J. V. O'Connor

Research output: Contribution to journalArticle

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Abstract

Recombinant human tumor necrosis factor (rTNFα) injected intravenously into rabbits produces a rapid-onset, monophasic fever indistinguishable from the fever produced by rIL-1. On a weight basis (1 μg/kg) rTNFα and rIL-1 produce the same amount of fever and induce comparable levels of PGE2 in rabbit hypothalamic cells in vitro; like IL-1, TNF fever is blocked by drugs that inhibit cyclooxygenase. At higher doses (10 μg/kg) rTNFα produces biphasic fevers. The first fever reaches peak elevation 45-55 min after bolus injection and likely represents a direct action on the thermoregulatory center. During the second fever peak (3 h later), a circulating endogenous pyrogen can be shown present using passive transfer of plasma into fresh rabbits. This likely represents the in vivo induction of IL-1. In vitro, rTNFα induces the release of IL-1 activity from human mononuclear cells with maximal production observed at 50-100 ng/ml of rTNFα. In addition, rTNFα and rIFN-γ have a synergistic effect on IL-1 production. The biological activity of rTNFα could be distinguished from IL-1 in three ways: (a) the monophasic pyrogenic activity of rIL-1 was destroyed at 70°C, whereas rTNFα remained active; (b) anti-IL-1 neutralized IL-1 but did not recognize rTNFα or natural cachectin nor neutralize its cytotoxic effect; and (c) unlike IL-1, rTNFα was not active in the mitogen-stimulated T cell proliferation assay. The possibility that endotoxin was responsible for rTNFα fever and/or the induction of IL-1 was ruled-out in several studies: (a) rTNFα produced fever in the endotoxin-resistant C3H/HeJ mice; (b) the IL-1-inducing property of rTNFα was destroyed either by heat (70°C) or trypsinization, and was unaffected by polymyxin B; (c) pyrogenic tolerance to daily injections of rTNFα did not occur; (d) levels of endotoxin, as determined in the Limulus amebocyte lysate, were below the minimum rabbit pyrogen dose; and (e) these levels of endotoxin were confirmed by gas chromatography/mass spectrometry analysis for the presence of β-hydroxymyristic acid. Although rTNFα is not active in T cell proliferation assays, it may mimic IL-1 in a T cell assay, since high concentrations of rTNFα induced IL-1 from epithelial or macrophagic cells in the thymocyte preparations. These studies show that TNF (cachectin) is another endogenous pyrogen which, like IL-1 and IFN-α, directly stimulate hypothalamic PGE2 synthesis. In addition, rTNFα is an endogenous inducer of IL-1. Together, these results support the concept that the febrile response to infection is a fundamental event in host defense and the induction of fever by endogenously produced molecules is not imparted to a single substance.

Original languageEnglish (US)
Pages (from-to)1433-1450
Number of pages18
JournalJournal of Experimental Medicine
Volume163
Issue number6
StatePublished - 1986

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Interleukin-1
Tumor Necrosis Factor-alpha
Fever
Endotoxins
Rabbits
human TNF protein
leukocyte endogenous mediator
T-Lymphocytes
Dinoprostone
Cell Proliferation
Pyrogens
Horseshoe Crabs
Polymyxin B
Injections
Inbred C3H Mouse
Thymocytes
Prostaglandin-Endoperoxide Synthases
Mitogens
Human Activities
Gas Chromatography-Mass Spectrometry

ASJC Scopus subject areas

  • Immunology

Cite this

Dinarello, C. A., Cannon, J. G., Wolff, S. M., Bernheim, H. A., Beutler, B., Cerami, A., ... O'Connor, J. V. (1986). Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1. Journal of Experimental Medicine, 163(6), 1433-1450.

Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1. / Dinarello, C. A.; Cannon, J. G.; Wolff, S. M.; Bernheim, H. A.; Beutler, B.; Cerami, A.; Figari, I. S.; Palladino, M. A.; O'Connor, J. V.

In: Journal of Experimental Medicine, Vol. 163, No. 6, 1986, p. 1433-1450.

Research output: Contribution to journalArticle

Dinarello, CA, Cannon, JG, Wolff, SM, Bernheim, HA, Beutler, B, Cerami, A, Figari, IS, Palladino, MA & O'Connor, JV 1986, 'Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1', Journal of Experimental Medicine, vol. 163, no. 6, pp. 1433-1450.
Dinarello, C. A. ; Cannon, J. G. ; Wolff, S. M. ; Bernheim, H. A. ; Beutler, B. ; Cerami, A. ; Figari, I. S. ; Palladino, M. A. ; O'Connor, J. V. / Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1. In: Journal of Experimental Medicine. 1986 ; Vol. 163, No. 6. pp. 1433-1450.
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abstract = "Recombinant human tumor necrosis factor (rTNFα) injected intravenously into rabbits produces a rapid-onset, monophasic fever indistinguishable from the fever produced by rIL-1. On a weight basis (1 μg/kg) rTNFα and rIL-1 produce the same amount of fever and induce comparable levels of PGE2 in rabbit hypothalamic cells in vitro; like IL-1, TNF fever is blocked by drugs that inhibit cyclooxygenase. At higher doses (10 μg/kg) rTNFα produces biphasic fevers. The first fever reaches peak elevation 45-55 min after bolus injection and likely represents a direct action on the thermoregulatory center. During the second fever peak (3 h later), a circulating endogenous pyrogen can be shown present using passive transfer of plasma into fresh rabbits. This likely represents the in vivo induction of IL-1. In vitro, rTNFα induces the release of IL-1 activity from human mononuclear cells with maximal production observed at 50-100 ng/ml of rTNFα. In addition, rTNFα and rIFN-γ have a synergistic effect on IL-1 production. The biological activity of rTNFα could be distinguished from IL-1 in three ways: (a) the monophasic pyrogenic activity of rIL-1 was destroyed at 70°C, whereas rTNFα remained active; (b) anti-IL-1 neutralized IL-1 but did not recognize rTNFα or natural cachectin nor neutralize its cytotoxic effect; and (c) unlike IL-1, rTNFα was not active in the mitogen-stimulated T cell proliferation assay. The possibility that endotoxin was responsible for rTNFα fever and/or the induction of IL-1 was ruled-out in several studies: (a) rTNFα produced fever in the endotoxin-resistant C3H/HeJ mice; (b) the IL-1-inducing property of rTNFα was destroyed either by heat (70°C) or trypsinization, and was unaffected by polymyxin B; (c) pyrogenic tolerance to daily injections of rTNFα did not occur; (d) levels of endotoxin, as determined in the Limulus amebocyte lysate, were below the minimum rabbit pyrogen dose; and (e) these levels of endotoxin were confirmed by gas chromatography/mass spectrometry analysis for the presence of β-hydroxymyristic acid. Although rTNFα is not active in T cell proliferation assays, it may mimic IL-1 in a T cell assay, since high concentrations of rTNFα induced IL-1 from epithelial or macrophagic cells in the thymocyte preparations. These studies show that TNF (cachectin) is another endogenous pyrogen which, like IL-1 and IFN-α, directly stimulate hypothalamic PGE2 synthesis. In addition, rTNFα is an endogenous inducer of IL-1. Together, these results support the concept that the febrile response to infection is a fundamental event in host defense and the induction of fever by endogenously produced molecules is not imparted to a single substance.",
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TY - JOUR

T1 - Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1

AU - Dinarello, C. A.

AU - Cannon, J. G.

AU - Wolff, S. M.

AU - Bernheim, H. A.

AU - Beutler, B.

AU - Cerami, A.

AU - Figari, I. S.

AU - Palladino, M. A.

AU - O'Connor, J. V.

PY - 1986

Y1 - 1986

N2 - Recombinant human tumor necrosis factor (rTNFα) injected intravenously into rabbits produces a rapid-onset, monophasic fever indistinguishable from the fever produced by rIL-1. On a weight basis (1 μg/kg) rTNFα and rIL-1 produce the same amount of fever and induce comparable levels of PGE2 in rabbit hypothalamic cells in vitro; like IL-1, TNF fever is blocked by drugs that inhibit cyclooxygenase. At higher doses (10 μg/kg) rTNFα produces biphasic fevers. The first fever reaches peak elevation 45-55 min after bolus injection and likely represents a direct action on the thermoregulatory center. During the second fever peak (3 h later), a circulating endogenous pyrogen can be shown present using passive transfer of plasma into fresh rabbits. This likely represents the in vivo induction of IL-1. In vitro, rTNFα induces the release of IL-1 activity from human mononuclear cells with maximal production observed at 50-100 ng/ml of rTNFα. In addition, rTNFα and rIFN-γ have a synergistic effect on IL-1 production. The biological activity of rTNFα could be distinguished from IL-1 in three ways: (a) the monophasic pyrogenic activity of rIL-1 was destroyed at 70°C, whereas rTNFα remained active; (b) anti-IL-1 neutralized IL-1 but did not recognize rTNFα or natural cachectin nor neutralize its cytotoxic effect; and (c) unlike IL-1, rTNFα was not active in the mitogen-stimulated T cell proliferation assay. The possibility that endotoxin was responsible for rTNFα fever and/or the induction of IL-1 was ruled-out in several studies: (a) rTNFα produced fever in the endotoxin-resistant C3H/HeJ mice; (b) the IL-1-inducing property of rTNFα was destroyed either by heat (70°C) or trypsinization, and was unaffected by polymyxin B; (c) pyrogenic tolerance to daily injections of rTNFα did not occur; (d) levels of endotoxin, as determined in the Limulus amebocyte lysate, were below the minimum rabbit pyrogen dose; and (e) these levels of endotoxin were confirmed by gas chromatography/mass spectrometry analysis for the presence of β-hydroxymyristic acid. Although rTNFα is not active in T cell proliferation assays, it may mimic IL-1 in a T cell assay, since high concentrations of rTNFα induced IL-1 from epithelial or macrophagic cells in the thymocyte preparations. These studies show that TNF (cachectin) is another endogenous pyrogen which, like IL-1 and IFN-α, directly stimulate hypothalamic PGE2 synthesis. In addition, rTNFα is an endogenous inducer of IL-1. Together, these results support the concept that the febrile response to infection is a fundamental event in host defense and the induction of fever by endogenously produced molecules is not imparted to a single substance.

AB - Recombinant human tumor necrosis factor (rTNFα) injected intravenously into rabbits produces a rapid-onset, monophasic fever indistinguishable from the fever produced by rIL-1. On a weight basis (1 μg/kg) rTNFα and rIL-1 produce the same amount of fever and induce comparable levels of PGE2 in rabbit hypothalamic cells in vitro; like IL-1, TNF fever is blocked by drugs that inhibit cyclooxygenase. At higher doses (10 μg/kg) rTNFα produces biphasic fevers. The first fever reaches peak elevation 45-55 min after bolus injection and likely represents a direct action on the thermoregulatory center. During the second fever peak (3 h later), a circulating endogenous pyrogen can be shown present using passive transfer of plasma into fresh rabbits. This likely represents the in vivo induction of IL-1. In vitro, rTNFα induces the release of IL-1 activity from human mononuclear cells with maximal production observed at 50-100 ng/ml of rTNFα. In addition, rTNFα and rIFN-γ have a synergistic effect on IL-1 production. The biological activity of rTNFα could be distinguished from IL-1 in three ways: (a) the monophasic pyrogenic activity of rIL-1 was destroyed at 70°C, whereas rTNFα remained active; (b) anti-IL-1 neutralized IL-1 but did not recognize rTNFα or natural cachectin nor neutralize its cytotoxic effect; and (c) unlike IL-1, rTNFα was not active in the mitogen-stimulated T cell proliferation assay. The possibility that endotoxin was responsible for rTNFα fever and/or the induction of IL-1 was ruled-out in several studies: (a) rTNFα produced fever in the endotoxin-resistant C3H/HeJ mice; (b) the IL-1-inducing property of rTNFα was destroyed either by heat (70°C) or trypsinization, and was unaffected by polymyxin B; (c) pyrogenic tolerance to daily injections of rTNFα did not occur; (d) levels of endotoxin, as determined in the Limulus amebocyte lysate, were below the minimum rabbit pyrogen dose; and (e) these levels of endotoxin were confirmed by gas chromatography/mass spectrometry analysis for the presence of β-hydroxymyristic acid. Although rTNFα is not active in T cell proliferation assays, it may mimic IL-1 in a T cell assay, since high concentrations of rTNFα induced IL-1 from epithelial or macrophagic cells in the thymocyte preparations. These studies show that TNF (cachectin) is another endogenous pyrogen which, like IL-1 and IFN-α, directly stimulate hypothalamic PGE2 synthesis. In addition, rTNFα is an endogenous inducer of IL-1. Together, these results support the concept that the febrile response to infection is a fundamental event in host defense and the induction of fever by endogenously produced molecules is not imparted to a single substance.

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