LPS-induced liver injury in D-galactosamine-sensitized mice requires secreted TNF-alpha and the TNF-p55 receptor

Am J Physiol Regul Integr Comp Physiol. 2000 May;278(5):R1202-9. doi: 10.1152/ajpregu.2000.278.5.R1202.

Abstract

Lipopolysaccharide and D-galactosamine induced lethality and apoptotic liver injury is dependent on endogenously produced tumor necrosis factor (TNF)-alpha. The present study was undertaken to determine whether membrane-associated or secreted TNF-alpha signaling through the p55 or p75 receptor was responsible for survival and hepatic injury after lipopolysaccharide administration in D-galactosamine-sensitized mice. Transgenic mice expressing null forms of TNF-alpha, the p55 and p75 receptor, and mice expressing only a cell-associated form of TNF-alpha were challenged with 8 mg D-galactosamine and 100 ng lipopolysaccharide. Mortality and apoptotic liver injury were only seen in wild-type and p75 knockout mice. p75 Knockout mice had significantly higher concentrations of plasma TNF-alpha than any other experimental group (P </= 0.05) and tended to have the highest mortality and liver injury. In contrast, p55 and TNF-alpha knockout mice and animals expressing only a cell-associated form of TNF-alpha exhibited no mortality or liver injury. We conclude that survival and apoptotic liver injury in response to lipopolysaccharide and D-galactosamine are dependent exclusively on secreted TNF-alpha signaling through the p55 receptor.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alanine Transaminase / blood
  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / physiology*
  • Apoptosis
  • Aspartate Aminotransferases / blood
  • Chemical and Drug Induced Liver Injury*
  • Female
  • Galactosamine*
  • Lipopolysaccharides*
  • Liver Diseases / mortality
  • Liver Diseases / physiopathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / physiology*
  • Receptors, Tumor Necrosis Factor, Type I
  • Tumor Necrosis Factor-alpha / deficiency
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Antigens, CD
  • Lipopolysaccharides
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Tumor Necrosis Factor-alpha
  • Galactosamine
  • Aspartate Aminotransferases
  • Alanine Transaminase