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

Br J Pharmacol. 1999 Sep;128(1):5-12. doi: 10.1038/sj.bjp.0702747.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Proteins / pharmacology
  • Chemical and Drug Induced Liver Injury / blood
  • Chemical and Drug Induced Liver Injury / metabolism*
  • Chemical and Drug Induced Liver Injury / mortality
  • Chemical and Drug Induced Liver Injury / pathology
  • Clodronic Acid / administration & dosage
  • Clodronic Acid / pharmacology
  • Dose-Response Relationship, Drug
  • Female
  • Galactosamine / antagonists & inhibitors
  • Galactosamine / pharmacology*
  • Hot Temperature
  • Interleukin-1 / blood
  • Interleukin-1 / pharmacology
  • Lipopolysaccharides / pharmacology*
  • Liposomes
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Macrophages / drug effects
  • Macrophages / physiology
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • Time Factors
  • Tumor Necrosis Factor-alpha / biosynthesis*
  • Tumor Necrosis Factor-alpha / toxicity
  • Uridine / pharmacology

Substances

  • Blood Proteins
  • Interleukin-1
  • Lipopolysaccharides
  • Liposomes
  • Tumor Necrosis Factor-alpha
  • Clodronic Acid
  • Galactosamine
  • Uridine