Ursodeoxycholic acid protects concanavalin A-induced mouse liver injury through inhibition of intrahepatic tumor necrosis factor-α and macrophage inflammatory protein-2 production

Abstract

Ursodeoxycholic acid (UDCA) is widely used for the therapy of liver dysfunction. In this study, we investigated the protective effect of UDCA in concanavalin A-induced mouse liver injury. The treatment with UDCA at oral doses of 50 and 150 mg/kg at 2 h before concanavalin A injection significantly reduced the elevated plasma levels of aminotransferases and the incidence of liver necrosis compared with concanavalin A-injected control group without affecting the concentrations of liver hydrophobic bile acids. UDCA significantly inhibited elevated levels of tumor necrosis factor-α (TNF-α), macrophage inflammatory protein-2 (MIP-2), and interleukin 6 (IL-6) in blood of concanavalin A-injected mice. To clarify the influence of UDCA on production of cytokines, we examined intrahepatic mRNA expressions and the protein levels of TNF-α, MIP-2, interferon-γ (IFN-γ), IL-4, IL-6, and IL-10 at 1 h after concanavalin A injection. The treatment with UDCA significantly decreased the intrahepatic levels of TNF- α and MIP-2, whereas this compound showed no clear effect on IFN-γ, IL-4, IL-6, or IL-10. Furthermore, UDCA significantly decreased myeloperoxidase activity as well as MIP-2 level in the liver and histological examination of liver tissue revealed that intrasinusoidal accumulation of neutrophils was decreased markedly by UDCA. In addition, UDCA significantly inhibited the production of TNF-α and MIP-2 when cultured with nonparenchymal and lymph node cells. In conclusion, these findings suggest that UDCA protects concanavalin A-induced liver injury in mice by inhibiting intrahepatic productions of TNF-α and MIP-2, and the infiltration of neutrophils into the liver.