Administration Of anti-Fas Antibody Research Articles

Low susceptibility of NC/Nga mice to tumor necrosis factor-α-mediated lethality and hepatocellular damage with d-galactosamine sensitization

The susceptibility of NC/Nga mice to tumor necrosis factor (TNF)-α was examined by using sensitization with d-galactosamine ( d-GalN). Administration of TNF-α and d-GalN killed none of the NC/Nga mice, whereas it killed all of the BALB/c mice. Treatment with TNF-α and d-GalN caused few hepatic lesions in NC/Nga mice but massive hepatocellular apoptosis in BALB/c mice. Unlike BALB/c mice, there was no elevation in caspase 3 and 8 activities in the livers of NC/Nga mice receiving TNF-α and d-GalN. On the other hand, administration of anti-Fas antibody definitely killed both NC/Nga and BALB/c mice via activation of caspases 3 and 8. Treatment with TNF-α and d-GalN led to translocation of nuclear factor (NF)-κB in NC/Nga and BALB/c mice. However, NF-κB translocation was sustained in NC/Nga mice, although it disappeared in BALB/c mice 7 h after the treatment. NF-κB inhibitors activated caspases 3 and 8, and enhanced TNF-α-mediated lethality in NC/Nga. Taken together, the low susceptibility of NC/Nga mice to TNF-α-mediated lethality was suggested to be responsible for the sustained NF-κB activation.

The Protective Effect of Cyclosporine A on Anti-Fas Antibody-Induced Hepatitis in Mice

The effect of cyclosporine A (CsA) on anti-Fas antibody-induced hepatitis was studied. The administration of anti-Fas antibody (250 μg/kg) to mice elevated plasma alanine aminotransferase (ALT) activity at 3 hr. This anti-Fas antibody-induced elevation of ALT was inhibited by treatment with CsA (10, 30 and 100 mg/kg) in a dose-dependent manner. Anti-Fas antibody administration elevated CPP32-like protease activity at 3 hr in mouse liver, and this elevation of CPP32-like activity was inhibited by treatment with CsA. The present results show that CsA treatment inhibits the anti-Fas antibody-induced apoptotic process of hepatitis, at least in part, by affecting a reaction upstream of CPP32-like protease activation.