Tumor Necrosis Factor α-Induced Hepatic Apoptosis and Hepatocyte Sensitization

Abstract

Tumor necrosis factor-α (TNFα) and Fas ligand are death factors that bind to their receptors, two TNF receptors (TNFR), TNFR1 and TNFR2, and Fas, respectively, and induce apoptosis in a variety of cell types. In galactosamine (GalN)-sensitized mice, hepatocyte apoptosis and liver failure were observed after injection of TNFα. On the contrary, neither apoptotic cell nor liver injury was shown in mice treated with TNFα alone. Histological analyses revealed that administration of GalN/TNF-α caused massive hemorrhagic liver damage and fragmented nuclei in hepatocytes, which were similar to those observed after the treatment with anti-Fas antibody. In contrast to hepatotoxicity by TNFα, however, GalN hardly sensitized the liver to injury by anti-Fas antibody. Compared with the GalN/TNFα model, most of the changes occurred earlier in the anti-Fas model. The expression of TNFR1 mRNA in the liver was up-regulated and reached a peak within 2h after GalN administration. However, the change of TNFR2 mRNA in the liver was less than that of TNFR1 mRNA. GalN treatment failed to affect TNFα-induced nuclear factor-κB activation. These results indicate that unlike apoptosis through Fas, TNFR-mediated liver cell apoptosis requires sensitization of the parenchymal cells. In the sensitization of hepatocytes to apoptosis, up-regulation of TNFR1 on hepatocytes could play an important role.