Stimulation of hepatocyte survival and suppression of CCl4-induced liver injury by the adenovirally introduced C/EBPβ gene

Gene therapy has attracted attention as a potentially effective alternative to liver transplantation for the treatment of hepatic failure. We chose the C/EBPβ gene, which plays vital roles in liver regeneration, as a candidate for gene therapy, and examined its effect on hepatocyte survival and the suppression of liver inflammation. C/EBPβ gene overexpression significantly maintained hepatocyte viability during 12 days of the culture. Urea synthesis ability, which is a liver-specific function, in Adv-C/EBPβ-infected hepatocytes was stably maintained during the culture, but the activity per cell was significantly lower than that in non-infected cells. On the contrary, DNA synthesis activity in Adv-C/EBPβ-infected hepatocytes was significantly higher than that in non-infected cells. COX-2 was induced in Adv-C/EBPβ-infected hepatocytes, and the addition of NS398, a specific inhibitor of COX-2, suppressed the viability-maintenance effect. COX-2 was thus shown to be involved in the survival effect of C/EBPβ gene. The introduction of the C/EBPβ gene into liver-damaged mice significantly suppressed the serum AST and ALT activities. These results indicate that C/EBPβ appears to be a survival factor under stressful conditions, and the introduction of the gene has therapeutic function against liver injury.