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 lpr 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.
Watanabe
Y
Y
Department of Biomolecular Engineering, Tokyo Institute of Technology, Yokohama, Japan.
Morita
M
M
Akaike
T
T
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000502:physiology; D056486:Chemical and Drug Induced Liver Injury; D003208:Concanavalin A; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008107:Liver Diseases / Q000473:pathology; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000502:physiology; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology; D019014:fas Receptor / Q000502:physiology*
D015815:Cell Adhesion Molecules; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D019014:fas Receptor; D003208:Concanavalin A; D054353:Perforin