Ursodeoxycholic acid protects concanavalin A-induced mouse liver injury through inhibition of intrahepatic tumor necrosis factor-alpha and macrophage inflammatory protein-2 production.
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.
Ishizaki
Kaoru
K
Research Laboratory III (Immunology), Pharmaceuticals Research Division, Mitsubishi Pharma Corporation, Yokohama, Japan. Ishizaki.Kaoru@mh.m-pharma.co.jp
Iwaki
Tomomichi
T
Kinoshita
Shuji
S
Koyama
Mamoru
M
Fukunari
Atsushi
A
Tanaka
Hideki
H
Tsurufuji
Makoto
M
Sakata
Kei
K
Maeda
Yasuhiro
Y
Imada
Teruaki
T
Chiba
Kenji
K
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D054426:Chemokine CXCL2 / Q000037:antagonists & inhibitors; D002756:Cholagogues and Choleretics / Q000008:administration & dosage / Q000494:pharmacology*; D003208:Concanavalin A / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D007371:Interferon-gamma / Q000187:drug effects / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020556:Neutrophil Infiltration / Q000187:drug effects; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D014580:Ursodeoxycholic Acid / Q000008:administration & dosage* / Q000494:pharmacology*
D054426:Chemokine CXCL2; D002756:Cholagogues and Choleretics; D007378:Interleukins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D014580:Ursodeoxycholic Acid; D007371:Interferon-gamma