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

Eur J Pharmacol. 2008 Jan 6;578(1):57-64. doi: 10.1016/j.ejphar.2007.08.031. Epub 2007 Sep 4.


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-alpha (TNF-alpha), 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-alpha, MIP-2, interferon-gamma (IFN-gamma), 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- alpha and MIP-2, whereas this compound showed no clear effect on IFN-gamma, 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-alpha 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-alpha and MIP-2, and the infiltration of neutrophils into the liver.

MeSH terms

  • Animals
  • Chemical and Drug Induced Liver Injury
  • Chemokine CXCL2 / antagonists & inhibitors
  • Cholagogues and Choleretics / administration & dosage
  • Cholagogues and Choleretics / pharmacology*
  • Concanavalin A / toxicity
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation / drug effects
  • Interferon-gamma / drug effects
  • Interferon-gamma / metabolism
  • Interleukins / metabolism
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Liver Diseases / drug therapy*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Neutrophil Infiltration / drug effects
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / metabolism
  • Ursodeoxycholic Acid / administration & dosage*
  • Ursodeoxycholic Acid / pharmacology*


  • Chemokine CXCL2
  • Cholagogues and Choleretics
  • Interleukins
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Concanavalin A
  • Ursodeoxycholic Acid
  • Interferon-gamma