Characterization and genetic analysis of the resistance of nonobese diabetic mice to tumor necrosis factor-alpha-mediated hepatocyte apoptosis and lethality.

摘要

Tumor necrosis factor-alpha (TNFα) is a proinflammatory cytokine produced primarily by activated macrophages during inflammation. TNFα is one of several proximal cytokines involved in both the activation of innate immunity, as well as in the initiation and polarization of the acquired immune response. TNFα is also capable of inducing hepatocyte apoptosis and irreversible liver injury, especially in the presence of transcriptional inhibition by D-galactosamine (D-GalN). Although many strains of mice are highly sensitive to the lethal effects of TNFα and D-GalN, we have demonstrated that the nonobese diabetic (NOD) mouse is highly resistant to LPS or recombinant human TNFα (rhTNFα) and D-GalN induced hepatocyte apoptosis, liver injury, and lethality. Therefore, the overall aim of this study was to more fully characterize the decreased responsiveness of NOD mice to TNFα and D-GalN induced lethality and liver injury, as well as to employ a genetic approach to identify potential loci involved in TNFα-mediated liver injury. By mating NOD and C57BL/6 (B6) strains, we demonstrated that (B6xNOD) F1 mice remained sensitive to both LPS or TNFα and D-GalN induced lethality, but exhibited intermediate hepatic apoptosis and injury responses when compared to parental strains, indicating that multiple genes may be involved in this phenotype. Quantitative trait locus (QTL) analysis was performed for mortality in female progeny from a backcross of (B6xNOD)F1 and NOD mice using a traditional genome-wide scan, revealing several significant loci on chromosomes 8, 11, and 13. In addition, caspase-3 activity, plasma IL-6, and plasma AST concentrations were also mapped in a separate QTL analysis, revealing suggestive loci on chromosomes 1, 5, and 16, with the chromosome 5 locus approaching significance. Candidate genes in these regions include several TNF receptor-associated signaling molecules, as well as diabetes susceptibility loci. Based on these findings, we can conclude that resistance to TNFα and D-GalN induced lethality and liver injury is a polygenic trait with at least three, and potentially up to six distinct contributing loci. Further analysis of candidate genes may provide a powerful tool for the study of related genes in humans.