Hyporesponsiveness of SPRET/Ei mice to lethal shock induced by tumor necrosis factor and implications for a TNF-based antitumor therapy

Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9340-5. doi: 10.1073/pnas.142293699. Epub 2002 Jun 27.

Abstract

Tumor necrosis factor (TNF) is a central mediator in lethal shock and an interesting cytokine for anticancer therapy. To inhibit TNF-induced lethal shock, it is important to identify protective genes. Here we demonstrate that the SPRET/Ei mouse strain, derived from Mus spretus, exhibits an extremely dominant resistance to TNF-induced lethal inflammation. An interspecific backcross experiment revealed that the TNF hyporesponse is linked to loci on chromosomes 2, 6, and 11. Treatment of inoculated tumors with TNF and IFN-gamma leads to regression and a highly reduced toxicity in (C57BL/6 x SPRET/Ei)F(1) mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death / drug effects
  • Drug Resistance
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Genetic Linkage
  • Interferon-gamma / therapeutic use
  • Interleukin-6 / biosynthesis
  • Macrophages, Peritoneal / drug effects
  • Macrophages, Peritoneal / immunology
  • Male
  • Melanoma, Experimental / drug therapy
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Muridae
  • Recombinant Proteins / therapeutic use
  • Recombinant Proteins / toxicity
  • Shock / etiology*
  • Tumor Necrosis Factor-alpha / therapeutic use
  • Tumor Necrosis Factor-alpha / toxicity*

Substances

  • Interleukin-6
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma