TNF-induced enterocyte apoptosis and detachment in mice: induction of caspases and prevention by a caspase inhibitor, ZVAD-fmk

Lab Invest. 1999 Apr;79(4):495-500.


Injection of mouse recombinant TNF to mice induced apoptosis and detachment of the enterocytes of the tip of the villi, evident after 30 to 90 minutes, which resulted in a shrinkage of the villi. Injection of TNF increased the expression of caspase 1, 2, 3, and 6 as well as of cathepsin D in the mucosal wall, which was maximal 30 minutes after TNF injection. Caspase 1 and 3 were not induced in TNFR1-deficient mice in which TNF does not induce apoptosis and detachment. The administration of a caspase inhibitor (ZVAD-fmk, 300 microg) decreased enterocyte detachment and apoptosis, as well as villus atrophy, whereas a caspase 3 inhibitor (Z-DEVD-cmk) had no effect. The results indicate that the induction of caspases by TNF is the cause of their detachment in the lumen and of the resulting villus atrophy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Chloromethyl Ketones / pharmacology*
  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism
  • Antigens, CD / physiology
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Cell Adhesion / drug effects
  • Cell Adhesion / physiology*
  • Cysteine Proteinase Inhibitors / pharmacology
  • DNA Fragmentation
  • Intestinal Mucosa / cytology*
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Knockout
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / metabolism
  • Receptors, Tumor Necrosis Factor / physiology
  • Receptors, Tumor Necrosis Factor, Type I
  • Recombinant Proteins / pharmacology
  • Tumor Necrosis Factor-alpha / pharmacology*


  • Amino Acid Chloromethyl Ketones
  • Antigens, CD
  • Cysteine Proteinase Inhibitors
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone