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

Josephs MD, Bahjat FR, Fukuzuka K, Ksontini R, Solorzano CC, Edwards CK, Tannahill CL, MacKay SL, Copeland EM, Moldawer LL
Am J Physiol Regul Integr Comp Physiol. 2000 278 (5): R1196-201

PMID: 10801287 · DOI:10.1152/ajpregu.2000.278.5.R1196

Tumor necrosis factor (TNF)-alpha and Fas ligand (FasL) are trimeric proteins that induce apoptosis through similar caspase-dependent pathways. Hepatocytes are particularly sensitive to inflammation-induced programmed cell death, although the contribution of TNF-alpha and/or FasL to this injury response is still unclear. Here, we report that D-galactosamine and lipopolysaccharide-induced liver injury in C57BL/6 mice is associated with increased hepatic expression of both TNF-alpha and FasL mRNA. Pretreatment of mice with a TNF-binding protein improved survival, reduced plasma aspartate aminotransferase concentrations, and attenuated the apoptotic liver injury, as determined histologically and by in situ 3' OH end labeling of fragmented nuclear DNA. In contrast, pretreatment of mice with a murine-soluble Fas fusion protein (Fasfp) had only minimal effect on survival, and apoptotic liver injury was either unaffected or exacerbated depending on the dose of Fasfp employed. Similarly, mice with a spontaneous mutation in FasL (B6Smn.C3H-Fasl(gld) derived from C57BL/6) were equally sensitive to D-galactosamine/lipopolysaccharide-induced shock. We conclude that the shock and apoptotic liver injury after D-galactosamine/lipopolysaccharide treatment are due primarily to TNF-alpha release, whereas increased FasL expression appears to contribute little to the mortality and hepatic injury.

MeSH Terms (23)

Animals Apoptosis Carrier Proteins Chemical and Drug Induced Liver Injury DNA Fragmentation Fas Ligand Protein fas Receptor Female Galactosamine Gene Expression Lipopolysaccharides Liver Liver Diseases Membrane Glycoproteins Mice Mice, Inbred C57BL Mutation Receptors, Tumor Necrosis Factor Receptors, Tumor Necrosis Factor, Type I Recombinant Fusion Proteins RNA, Messenger Tumor Necrosis Factor-alpha Tumor Necrosis Factor Decoy Receptors

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