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

Several models of tumor necrosis factor (TNF)/TNF-receptor 1 (TNF-R1)-depen dent liver injury in mice were investigated with respect to caspase-3-like protease activation representing a pivotal mechanism of apoptotic cell deat h. Injection of TNF or T-cell-activating agents (i.e., agonistic anti-CD3 a ntibody or staphylococcal enterotoxin B [SEB]) into galactosamine (GalN)-se nsitized mice caused TNF/TNF-R1-dependent liver injury. Intravenous concana valin 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 mic e. Consistently, the broad-spectrum caspase inhibitor, benzoyloxycarbonyl-v al-ala-asp-fluoromethylketone (zVADfmk), prevented TNF-mediated hepatotoxic ity in all GalN-dependent models, but failed to protect against Con A. Unde r transcriptional arrest, however, Con A induced TNF-R1-dependent, but not TNF-R2-dependent, activation of caspase-3-like proteases, and zVADfmk preve nted animals from Con A-mediated liver injury under this condition, Histolo gical analysis revealed distinct differences between Con A- and GalN/Con A- induced liver injury regarding apoptotic morphology of hepatocytes. We conc lude that impaired transcription induces a switch of Con A hepatotoxicity t oward a caspase-3-like protease-dependent pathway. The observation that the functional state of the transcriptional machinery decides whether TNF-driv en hepatocyte apoptosis involves activation of caspase-3-like proteases or alternative signaling pathways in vivo might be of relevance for the immuno pathology of the liver.