Concanavalin A hepatotoxicity in mice: tumor necrosis factor-mediated organ failure independent of caspase-3-like protease activation.

G Künstle; H Hentze; P G Germann; Gisa Tiegs; T Meergans; A Wendel

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, Vol. 30, No. 5, 5, 1999, p. 1241-1251.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Künstle, G, Hentze, H, Germann, PG, Tiegs, G, Meergans, T & Wendel, A 1999, 'Concanavalin A hepatotoxicity in mice: tumor necrosis factor-mediated organ failure independent of caspase-3-like protease activation.', HEPATOLOGY, vol. 30, no. 5, 5, pp. 1241-1251. <http://www.ncbi.nlm.nih.gov/pubmed/10534346?dopt=Citation>

APA

Künstle, G., Hentze, H., Germann, P. G., Tiegs, G., Meergans, T., & Wendel, A. (1999). Concanavalin A hepatotoxicity in mice: tumor necrosis factor-mediated organ failure independent of caspase-3-like protease activation. HEPATOLOGY, 30(5), 1241-1251. [5]. http://www.ncbi.nlm.nih.gov/pubmed/10534346?dopt=Citation

Vancouver

Künstle G, Hentze H, Germann PG, Tiegs G, Meergans T, Wendel A. Concanavalin A hepatotoxicity in mice: tumor necrosis factor-mediated organ failure independent of caspase-3-like protease activation. HEPATOLOGY. 1999;30(5):1241-1251. 5.

Bibtex

@article{6619f958bd384666a6eba63b58aa5068,

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.",

keywords = "Animals, Male, Mice, Mice, Inbred BALB C, Lipid Metabolism, Enzyme Activation, Specific Pathogen-Free Organisms, Apoptosis/drug effects, Caspase 3, Receptors, Tumor Necrosis Factor, Type II, Caspases/*metabolism, Antibodies/pharmacology, Receptors, Tumor Necrosis Factor, Type I, Receptors, Tumor Necrosis Factor/physiology, Amino Acid Chloromethyl Ketones/pharmacology, Antigens, CD/physiology, Antigens, CD3/physiology, Concanavalin A/*toxicity, Cysteine Proteinase Inhibitors/pharmacology, Enterotoxins/toxicity, Galactosamine/toxicity, Liver/drug effects/enzymology/*pathology, Staphylococcus aureus, Tumor Necrosis Factor-alpha/*physiology, Animals, Male, Mice, Mice, Inbred BALB C, Lipid Metabolism, Enzyme Activation, Specific Pathogen-Free Organisms, Apoptosis/drug effects, Caspase 3, Receptors, Tumor Necrosis Factor, Type II, Caspases/*metabolism, Antibodies/pharmacology, Receptors, Tumor Necrosis Factor, Type I, Receptors, Tumor Necrosis Factor/physiology, Amino Acid Chloromethyl Ketones/pharmacology, Antigens, CD/physiology, Antigens, CD3/physiology, Concanavalin A/*toxicity, Cysteine Proteinase Inhibitors/pharmacology, Enterotoxins/toxicity, Galactosamine/toxicity, Liver/drug effects/enzymology/*pathology, Staphylococcus aureus, Tumor Necrosis Factor-alpha/*physiology",

author = "G K{\"u}nstle and H Hentze and Germann, {P G} and Gisa Tiegs and T Meergans and A Wendel",

year = "1999",

language = "English",

volume = "30",

pages = "1241--1251",

journal = "HEPATOLOGY",

issn = "0270-9139",

publisher = "John Wiley and Sons Ltd",

number = "5",

}

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