Search tips
Search criteria 


Logo of jexpmedHomeEditorsContactInstructions for Authors
J Exp Med. 1987 March 1; 165(3): 657–663.
PMCID: PMC2188282

Lethal toxicity of lipopolysaccharide and tumor necrosis factor in normal and D-galactosamine-treated mice


The toxic properties of human recombinant tumor necrosis factor (TNF) were investigated in mice made hypersensitive to endotoxin by treatment with D-galactosamine. C3H/TifF mice treated with D-galactosamine were rendered sensitive to the lethal effects of submicrogram amounts of TNF. In the absence of D-galactosamine, TNF caused approximately 80% lethality with 500 micrograms. The duration of sensitization to TNF lasted up to 8 h after D-galactosamine administration, that towards LPS, up to 4 h. As with LPS, with TNF sensitization could be inhibited by uridine administered up to 2 h after D-galactosamine/TNF, showing that the early biochemical alterations in the liver known to be necessary for sensitization to LPS are also necessary for sensitization to TNF. In contrast to LPS, the toxicity of TNF was expressed also in D- galactosamine-treated endotoxin-resistant C3H/HeJ mice. The susceptibility of these mice to TNF was identical to that of endotoxin sensitive mice. In the absence of D-galactosamine the toxicity of TNF in C3H/HeJ mice was comparable to that obtained in C3H/TifF mice, being lethal with amounts of the order of 500 micrograms. The present results support the hypothesis that TNF is a mediator of lethal toxicity of endotoxin.

Full Text

The Full Text of this article is available as a PDF (462K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Galanos C, Freudenberg MA, Reutter W. Galactosamine-induced sensitization to the lethal effects of endotoxin. Proc Natl Acad Sci U S A. 1979 Nov;76(11):5939–5943. [PubMed]
  • Decker K, Keppler D. Galactosamine hepatitis: key role of the nucleotide deficiency period in the pathogenesis of cell injury and cell death. Rev Physiol Biochem Pharmacol. 1974;(71):77–106. [PubMed]
  • Freudenberg MA, Keppler D, Galanos C. Requirement for lipopolysaccharide-responsive macrophages in galactosamine-induced sensitization to endotoxin. Infect Immun. 1986 Mar;51(3):891–895. [PMC free article] [PubMed]
  • Beutler B, Milsark IW, Cerami AC. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science. 1985 Aug 30;229(4716):869–871. [PubMed]
  • Männel DN, Moore RN, Mergenhagen SE. Macrophages as a source of tumoricidal activity (tumor-necrotizing factor). Infect Immun. 1980 Nov;30(2):523–530. [PMC free article] [PubMed]
  • Kawakami M, Pekala PH, Lane MD, Cerami A. Lipoprotein lipase suppression in 3T3-L1 cells by an endotoxin-induced mediator from exudate cells. Proc Natl Acad Sci U S A. 1982 Feb;79(3):912–916. [PubMed]
  • Nawroth PP, Bank I, Handley D, Cassimeris J, Chess L, Stern D. Tumor necrosis factor/cachectin interacts with endothelial cell receptors to induce release of interleukin 1. J Exp Med. 1986 Jun 1;163(6):1363–1375. [PMC free article] [PubMed]
  • Beutler B, Mahoney J, Le Trang N, Pekala P, Cerami A. Purification of cachectin, a lipoprotein lipase-suppressing hormone secreted by endotoxin-induced RAW 264.7 cells. J Exp Med. 1985 May 1;161(5):984–995. [PMC free article] [PubMed]
  • Sultzer BM. Genetic control of leucocyte responses to endotoxin. Nature. 1968 Sep 21;219(5160):1253–1254. [PubMed]
  • Coutinho A, Forni L, Melchers F, Watanabe T. Genetic defect in responsiveness to the B cell mitogen lipopolysaccharide. Eur J Immunol. 1977 May;7(5):325–328. [PubMed]
  • McAdam KP, Ryan JL. C57BL/10/CR mice: nonresponders to activation by the lipid a moiety of bacterial lipopolysaccharide. J Immunol. 1978 Jan;120(1):249–253. [PubMed]
  • Galanos C, Lüderitz O, Westphal O. Preparation and properties of a standardized lipopolysaccharide from salmonella abortus equi (Novo-Pyrexal). Zentralbl Bakteriol Orig A. 1979 Apr;243(2-3):226–244. [PubMed]
  • Kawakami M, Cerami A. Studies of endotoxin-induced decrease in lipoprotein lipase activity. J Exp Med. 1981 Sep 1;154(3):631–639. [PMC free article] [PubMed]
  • Dinarello CA, Cannon JG, Wolff SM, Bernheim HA, Beutler B, Cerami A, Figari IS, Palladino MA, Jr, O'Connor JV. Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1. J Exp Med. 1986 Jun 1;163(6):1433–1450. [PMC free article] [PubMed]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press