Involvement of Fas/Fas ligand system-mediated apoptosis in the development of concanavalin A-induced hepatitis.
Concanavalin A (Con A)-induced hepatitis is an experimental hepatitis model in which hepatic injury is caused by the action of cytokines produced by T cells. Using IFN-gamma-deficient mice, we previously demonstrated that IFN-gamma plays a central role in Con A-induced hepatitis. Here, we show that development of the disease is completely suppressed in gld/gld mice, in which Fas ligand is defective. In contrast, suppression of the disease in Ipr/Ipr mice was incomplete, since a small amount of the fas mRNA was produced in these mice. The data indicate that activation of the Fas/Fas ligand system is a necessary step in the development of Con A-induced hepatitis. Furthermore, we found that not only fas but also caspase-1 expression was reduced in IFN-gamma-deficient mice. Since caspase-1 is an integral component of Fas signal transduction, these observations suggest that IFN-gamma-induced activation of both fas and caspase-1 expression causes enhancement of hepatocyte apoptosis resulting in the development of hepatitis.
Tagawa
Y
Y
Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Japan.
Kakuta
S
S
Iwakura
Y
Y
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D003208:Concanavalin A / Q000276:immunology / Q000633:toxicity*; D053222:Fas Ligand Protein; D006520:Hepatitis, Animal / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D017354:Point Mutation; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D019014:fas Receptor / Q000235:genetics / Q000276:immunology*
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D019014:fas Receptor; D003208:Concanavalin A; D007371:Interferon-gamma