Effect of ursodeoxycholic acid on expression of Fas ligand and tumor necrosis factor-alpha in the liver of mice with acute graft-versus-host disease

Abstract

Background: The Fas-Fas-ligand (FasL) system and tumor necrosis factor-alpha (TNF-α) are involved in immune-mediated liver injury. They have also been shown to play a critical role in the pathogenesis of acute graft-versus-host disease (GVHD). Objective: The aim of the present study was to determine whether continuous oral administration of ursodeoxycholic acid (UDCA) could inhibit Fas-FasL and TNF-α expression in the liver of mice with acute GVHD. Methods: BDF1 mice were assigned to 1 of 2 groups. In the UDCA group, mice were administered UDCA 50 mg/kg once daily for 3 weeks via gastric tube in 200 μL of sodium hydroxide (1 mol/L at pH 8.3). In the control (placebo) group, mice were administered 200 μL of sodium hydroxide (1 mol/L at pH 8.3) for 3 weeks. Acute GVHD was induced 1 week after administration of UDCA or placebo. To determine the serum concentration of TNF-α, serum was assayed using an enzyme-linked immunosorbent assay. A reverse transcribed polymerase chain reaction procedure was performed to investigate the expression of FasL and TNF-α mRNA in the liver. Individual bile acids were separated and quantified by high-performance liquid chromatography to determine if UDCA composition was enriched in the bile after administration of UDCA. Results for group means were compared using the Student t test. Significance was set at P < 0.05. Results: There were 5 mice in each group. Oral administration of UDCA resulted in a 34.0% enrichment of UDCA in the serum of mice given UDCA and in 1.9% of mice given placebo. The mean UDCA composition in the bile was 32.1% in mice given UDCA and 9.2% in mice given placebo. Although treatment with UDCA did not affect phenotypic change of hepatic lymphocytes caused by acute GVHD, it significantly ( P < 0.05) inhibited the augmentation of FasL and TNF-α expression in the liver. FasL and TNF-α mRNA decreased from 0.3 to 0.18 and from 1.30 to 0.70, respectively. Treatment with UDCA also significantly ( P < 0.05) suppressed the serum concentration of TNF-α in mice with acute GVHD (23 pg/mL, placebo group; 14 pg/mL, UDCA group). Conclusions: These findings suggest that UDCA suppresses both FasL- and TNF-α-mediated hepatotoxic pathways in acute GVHD-induced liver injury. Further studies are needed to determine the role of UDCA plus immunosuppressive drugs in liver injury caused by acute GVHD.