Abstract
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
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Chloromethyl Ketones / pharmacology*
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Animals
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Antigens, CD / genetics
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Antigens, CD / metabolism
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Antigens, CD / physiology
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Apoptosis / drug effects
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Apoptosis / physiology*
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Cell Adhesion / drug effects
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Cell Adhesion / physiology*
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Cysteine Proteinase Inhibitors / pharmacology
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DNA Fragmentation
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Intestinal Mucosa / cytology*
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Intestinal Mucosa / drug effects
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Intestinal Mucosa / pathology
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Mice
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Mice, Inbred C57BL
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Mice, Inbred CBA
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Mice, Knockout
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Receptors, Tumor Necrosis Factor / genetics
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Receptors, Tumor Necrosis Factor / metabolism
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Receptors, Tumor Necrosis Factor / physiology
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Receptors, Tumor Necrosis Factor, Type I
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Recombinant Proteins / pharmacology
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Tumor Necrosis Factor-alpha / pharmacology*
Substances
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Amino Acid Chloromethyl Ketones
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Antigens, CD
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Cysteine Proteinase Inhibitors
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Receptors, Tumor Necrosis Factor
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Receptors, Tumor Necrosis Factor, Type I
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Recombinant Proteins
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Tumor Necrosis Factor-alpha
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benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone