Concanavalin A induces perforin-mediated but not Fas-mediated hepatic injury

Concanavalin A (Con A) induces T-cell-mediated hepatic injury in vivo although Con A-stimulated lymphocytes are not cytotoxic to normal hepatocytes in vitro, This contradiction makes the mechanism of Con A-induced hepatitis elusive. In this study, we demonstrate that Con A but not tumor necrosis factor (alpha (TNF-alpha), interferon gamma (IFN-gamma), or actinomycin D (ActD) induced the susceptibility of hepatocytes to activated autologous lymphocyte cytotoxicity, Con A sensitized hepatocytes within 30 minutes after the stimulation in a dose-dependent fashion, The cytotoxicity was dose-dependently inhibited by either a Con A ligand, alpha-methyl mannoside, or a perforin inhibitor, concanamycin A (CMA), but not by anti-Fas ligand antiserum, In addition, Con A-treated hepatocytes were not sensitive to autologous activated lymphocytes from a perforin-deficient mouse, while hepatocytes from 1pr mice were sensitized by Con A In fact, Con A did not induce Liver injury in perforin-deficient mice within the concentration employed in this study, Therefore, we conclude that the cytotoxicity was mediated through perforin/granzymes but not through the Fas/Fas ligand pathway, The cytotoxicity was inhibited by anti-intercellular adhesion molecule-1 (ICAM-1)/LFA-1 antibodies, but not by anti-VCAM-1/VLA-4 antibodies, both in vitro and in vivo, The cytotoxicity appears to be caused by CD8(+) T cells; however, the cytokines from activated CD4(+) T cells play a critical role in the pathogenesis of the hepatitis in vivo because administration of anti-IFN-gamma antibodies inhibited the occurrence of the hepatitis, In conclusion, Con A-induced hepatitis is thought to be dominantly mediated by a perforin-dependent pathway through ICAM-1/LFA-1 interaction.