Inhibition of Cyclic Adenosine Monophosphate (cAMP)-response Element-binding Protein (CREB)-binding Protein (CBP)/@b-Catenin Reduces Liver Fibrosis in Mice

摘要

Wnt/@b-catenin is involved in every aspect of embryonic development and in the pathogenesis of many human diseases, and is also implicated in organ fibrosis. However, the role of @b-catenin-mediated signaling on liver fibrosis remains unclear. To explore this issue, the effects of PRI-724, a selective inhibitor of the cAMP-response element-binding protein-binding protein (CBP)/@b-catenin interaction, on liver fibrosis were examined using carbon tetrachloride (CCl"4)- or bile duct ligation (BDL)-induced mouse liver fibrosis models. Following repetitive CCl"4 administrations, the nuclear translocation of @b-catenin was observed only in the non-parenchymal cells in the liver. PRI-724 treatment reduced the fibrosis induced by CCl"4 or BDL. C-82, an active form of PRI-724, inhibited the activation of isolated primary mouse quiescent hepatic stellate cells (HSCs) and promoted cell death in culture-activated HSCs. During the fibrosis resolution period, an increase in F4/80^+ CD11b^+ and Ly6C^l^o^w CD11b^+ macrophages was induced by CCl"4 and was sustained for two weeks thereafter, even after having stopped CCl"4 treatment. PRI-724 accelerated the resolution of CCl"4-induced liver fibrosis, and this was accompanied by increased matrix metalloproteinase (MMP)-9, MMP-2, and MMP-8 expression in intrahepatic leukocytes. In conclusion, targeting the CBP/@b-catenin interaction may become a new therapeutic strategy in treating liver fibrosis.