Concanavalin A hepatotoxicity in mice: tumor necrosis factor-mediated organ failure independent of caspase-3-like protease activation.
Standard
Concanavalin A hepatotoxicity in mice: tumor necrosis factor-mediated organ failure independent of caspase-3-like protease activation. / Künstle, G; Hentze, H; Germann, P G; Tiegs, Gisa; Meergans, T; Wendel, A.
in: HEPATOLOGY, Jahrgang 30, Nr. 5, 5, 1999, S. 1241-1251.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Concanavalin A hepatotoxicity in mice: tumor necrosis factor-mediated organ failure independent of caspase-3-like protease activation.
AU - Künstle, G
AU - Hentze, H
AU - Germann, P G
AU - Tiegs, Gisa
AU - Meergans, T
AU - Wendel, A
PY - 1999
Y1 - 1999
N2 - 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.
AB - 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.
KW - Animals
KW - Male
KW - Mice
KW - Mice, Inbred BALB C
KW - Lipid Metabolism
KW - Enzyme Activation
KW - Specific Pathogen-Free Organisms
KW - Apoptosis/drug effects
KW - Caspase 3
KW - Receptors, Tumor Necrosis Factor, Type II
KW - Caspases/metabolism
KW - Antibodies/pharmacology
KW - Receptors, Tumor Necrosis Factor, Type I
KW - Receptors, Tumor Necrosis Factor/physiology
KW - Amino Acid Chloromethyl Ketones/pharmacology
KW - Antigens, CD/physiology
KW - Antigens, CD3/physiology
KW - Concanavalin A/toxicity
KW - Cysteine Proteinase Inhibitors/pharmacology
KW - Enterotoxins/toxicity
KW - Galactosamine/toxicity
KW - Liver/drug effects/enzymology/pathology
KW - Staphylococcus aureus
KW - Tumor Necrosis Factor-alpha/physiology
KW - Animals
KW - Male
KW - Mice
KW - Mice, Inbred BALB C
KW - Lipid Metabolism
KW - Enzyme Activation
KW - Specific Pathogen-Free Organisms
KW - Apoptosis/drug effects
KW - Caspase 3
KW - Receptors, Tumor Necrosis Factor, Type II
KW - Caspases/metabolism
KW - Antibodies/pharmacology
KW - Receptors, Tumor Necrosis Factor, Type I
KW - Receptors, Tumor Necrosis Factor/physiology
KW - Amino Acid Chloromethyl Ketones/pharmacology
KW - Antigens, CD/physiology
KW - Antigens, CD3/physiology
KW - Concanavalin A/toxicity
KW - Cysteine Proteinase Inhibitors/pharmacology
KW - Enterotoxins/toxicity
KW - Galactosamine/toxicity
KW - Liver/drug effects/enzymology/pathology
KW - Staphylococcus aureus
KW - Tumor Necrosis Factor-alpha/physiology
M3 - SCORING: Journal article
VL - 30
SP - 1241
EP - 1251
JO - HEPATOLOGY
JF - HEPATOLOGY
SN - 0270-9139
IS - 5
M1 - 5
ER -