title: Concanavalin A hepatotoxicity in mice: tumor necrosis factor-mediated organ failure independent of caspase-3-like protease activation.
abstract: Several models of tumor necrosis factor (TNF)/TNF-receptor 1 (TNF-R1)-dependent liver injury in mice were investigated with respect to caspase-3-like protease activation representing a pivotal mechanism of apoptotic cell death. Injection of TNF or T-cell-activating agents (i.e., agonistic anti-CD3 antibody or staphylococcal enterotoxin B [SEB]) into galactosamine (GalN)-sensitized mice caused TNF/TNF-R1-dependent liver injury. Intravenous concanavalin A (Con A) alone induced TNF-mediated hepatotoxicity dependent on both TNF-R1 and TNF-R2. Hepatic caspase-3-like proteases were activated in GalN/TNF, GalN/anti-CD3, or GalN/SEB-treated mice, but not in Con A-treated mice. Consistently, the broad-spectrum caspase inhibitor, benzoyloxycarbonyl-val-ala-asp-fluoromethylketone (zVADfmk), prevented TNF-mediated hepatotoxicity in all GalN-dependent models, but failed to protect against Con A. Under transcriptional arrest, however, Con A induced TNF-R1-dependent, but not TNF-R2-dependent, activation of caspase-3-like proteases, and zVADfmk prevented animals from Con A-mediated liver injury under this condition. Histological analysis revealed distinct differences between Con A- and GalN/Con A-induced liver injury regarding apoptotic morphology of hepatocytes. We conclude that impaired transcription induces a switch of Con A hepatotoxicity toward a caspase-3-like protease-dependent pathway. The observation that the functional state of the transcriptional machinery decides whether TNF-driven hepatocyte apoptosis involves activation of caspase-3-like proteases or alternative signaling pathways in vivo might be of relevance for the immunopathology of the liver.
authors.affiliation: Biochemical Pharmacology, Faculty of Biology, University of Konstanz, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Künstle
authors.forename: H
authors.initials: H
authors.lastname: Hentze
authors.forename: P G
authors.initials: PG
authors.lastname: Germann
authors.forename: G
authors.initials: G
authors.lastname: Tiegs
authors.forename: T
authors.initials: T
authors.lastname: Meergans
authors.forename: A
authors.initials: A
authors.lastname: Wendel
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects; D017252:CD3 Complex / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D003208:Concanavalin A / Q000633:toxicity*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004768:Enterotoxins / Q000633:toxicity; D004789:Enzyme Activation; D005688:Galactosamine / Q000633:toxicity; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D013047:Specific Pathogen-Free Organisms; D013211:Staphylococcus aureus; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000906:Antibodies; D015703:Antigens, CD; D017252:CD3 Complex; D015853:Cysteine Proteinase Inhibitors; D004768:Enterotoxins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D003208:Concanavalin A; C031818:enterotoxin B, staphylococcal; D005688:Galactosamine; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases