Scripps VIVO scripps research logo

  • Index
  • Log in
  • Home
  • People
  • Organizations
  • Research
  • Events
Search form

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

Academic Article
uri icon
  • Overview
  • Identity
  • Additional Document Info
  • View All
scroll to property group menus

Overview

authors

  • Dinarello, C. A.
  • Cannon, J. G.
  • Wolff, S. M.
  • Bernheim, H. A.
  • Beutler, Bruce
  • Cerami, A.
  • Figari, I. S.
  • Palladino, M. A.
  • Oconnor, J. V.

publication date

  • June 1986

journal

  • Journal of Experimental Medicine  Journal

abstract

  • Recombinant human tumor necrosis factor (rTNF alpha) injected intravenously into rabbits produces a rapid-onset, monophasic fever indistinguishable from the fever produced by rIL-1. On a weight basis (1 microgram/kg) rTNF alpha 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 micrograms/kg) rTNF alpha 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, rTNF alpha induces the release of IL-1 activity from human mononuclear cells with maximal production observed at 50-100 ng/ml of rTNF alpha. In addition, rTNF alpha and rIFN-gamma have a synergistic effect on IL-1 production. The biological activity of rTNF alpha could be distinguished from IL-1 in three ways: the monophasic pyrogenic activity of rIL-1 was destroyed at 70 degrees C, whereas rTNF alpha remained active; anti-IL-1 neutralized IL-1 but did recognize rTNF alpha or natural cachectin nor neutralize its cytotoxic effect; and unlike IL-1, rTNF alpha was not active in the mitogen-stimulated T cell proliferation assay. The possibility that endotoxin was responsible for rTNF alpha fever and/or the induction of IL-1 was ruled-out in several studies: rTNF alpha produced fever in the endotoxin-resistant C3H/HeJ mice; the IL-1-inducing property of rTNF alpha was destroyed either by heat (70 degrees C) or trypsinization, and was unaffected by polymyxin B; pyrogenic tolerance to daily injections of rTNF alpha did not occur; levels of endotoxin, as determined in the Limulus amebocyte lysate, were below the minimum rabbit pyrogen dose; and these levels of endotoxin were confirmed by gas chromatography/mass spectrometry analysis for the presence of beta-hydroxymyristic acid. Although rTNF alpha is not active in T cell proliferation assays, it may mimic IL-1 in a T cell assay, since high concentrations of rTNF alpha 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-alpha, directly stimulate hypothalamic PGE2 synthesis. In addition, rTNF alpha is an endogenous inducer of IL-1.(ABSTRACT TRUNCATED AT 400 WORDS)

subject areas

  • Animals
  • Dinoprostone
  • Endotoxins
  • Fever
  • Glycoproteins
  • Interleukin-1
  • Mice
  • Monocytes
  • Prostaglandins E
  • Pyrogens
  • Rabbits
  • Recombinant Proteins
  • Stimulation, Chemical
  • Tumor Necrosis Factor-alpha
scroll to property group menus

Identity

PubMed Central ID

  • PMC2188124

International Standard Serial Number (ISSN)

  • 0022-1007

Digital Object Identifier (DOI)

  • 10.1084/jem.163.6.1433

PubMed ID

  • 3486936
scroll to property group menus

Additional Document Info

start page

  • 1433

end page

  • 1450

volume

  • 163

issue

  • 6

©2021 The Scripps Research Institute | Terms of Use | Powered by VIVO

  • About
  • Contact Us
  • Support