Lipopolysaccharide and D-galactosamine-induced hepatic injury is mediated by TNF-alpha and not by Fas ligand

Tumor necrosis factor (TNF)-alpha and Fas ligand (FasL) are trimeric protei ns that induce apoptosis through similar caspase-dependent pathways. Hepato cytes are particularly sensitive to inflammation-induced programmed cell de ath, although the contribution of TNF-alpha and/or Fast to this injury resp onse is still unclear. Here, we report that D-galactosamine and lipopolysac charide-induced liver injury in C57BL/6 mice is associated with increased h epatic expression of both TNF-alpha and Fast mRNA. Pretreatment of mice wit h a TNF-binding protein improved survival, reduced plasma aspartate aminotr ansferase concentrations, and attenuated the apoptotic liver injury, as det ermined histologically and by in situ 3' OH end labeling of fragmented nucl ear DNA. In contrast, pretreatment of mice with a murine-soluble Fas fusion protein (Fasfp) had only minimal effect on survival, and apoptotic liver i njury was either unaffected or exacerbated depending on the dose of Fasfp e mployed. Similarly, mice with a spontaneous mutation in Fast (B6Smn.C3H-Fas l(gld) derived from C57BL/6) were equally sensitive to D-galactosamine/lipo polysaccharide-induced shock. We conclude that the shock and apoptotic live r injury after D-galactosamine/lipopolysaccharide treatment are due primari ly to TNF-alpha release, whereas increased Fast expression appears to contr ibute little to the mortality and hepatic injury.