Enhancement by galactosamine of lipopolysaccharide(LPS)-induced tumour necrosis factor production and lethality: Its suppression by LPS pretreatment

Yasuo Endo, Masahiko Shibazaki, Kouji Yamaguchi, Kenzou Kai, Shunji Sugawara, Haruhiko Takada, Hideaki Kikuchi, Katsuo Kumagai

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55 Citations (Scopus)


1 D-Galactosamine (GalN) depletes UTP primarily in the liver, resulting in decreased RNA synthesis in hepatocytes. Co-injection of GalN and lipopolysaccharide (LPS) into mice produces fulminant hepatitis with severe hepatic congestion, resulting in rapid death. Although the underlying mechanism is uncertain, GalN enhances the sensitivity to tumour necrosis factor (TNF). Administration of uridine (a precursor of UTP) prior injection of either LPS itself or interleukin-1 (IL-1) reduces the lethality of GalN + LPS. The present study focused on the effects of these agents on TNF production. 2 Intraperitoneal injection of GalN + LPS into mice greatly elevated serum TNF. Although large doses of LPS alone also greatly elevated serum TNF, LPS itself induced neither hepatic congestion nor rapid death. Administration of a macrophage depletor, liposomes encapsulated with dichloromethylene bisphosphonate, reduced both the TNF production and mortality induced by GalN + LPS. 3 Uridine, when injected 0.5 h after the injection of GalN + LPS, reduced the production of TNF. Prior injection of LPS, but not of IL-1, also reduced this TNF production. 4 Serum from LPS-injected mice reduced the TNF production induced by GalN + LPS, but it was less effective at reducing the lethality. Its ability to reduce TNF production was abolished by heat-treatment. 5 We hypothesize that a factor inhibiting TNF production by macrophages is produced by hepatocytes in response to LPS. Possibly, production of this hepatocyte-derived TNF-down-regulator (TNF-DRh) may be: (i) inhibited by GalN, causing over-production of TNF by macrophages and (ii) stimulated by LPS-pretreatment (and restored by uridine), causing reduced TNF production.

Original languageEnglish
Pages (from-to)5-12
Number of pages8
JournalBritish Journal of Pharmacology
Issue number1
Publication statusPublished - 1999


  • Endotoxin shock
  • Galactosamine
  • Hepatitis
  • Inhibitor of TNF synthesis
  • Interleukin-1 (IL-1)
  • Lipopolysaccharide
  • Tumour necrosis factor (TNF)

ASJC Scopus subject areas

  • Pharmacology


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