Wnt/β-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 β-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)/β-catenin interaction, on liver fibrosis were examined using carbon tetrachloride (CCl4)- or bile duct ligation (BDL)-induced mouse liver fibrosis models. Following repetitive CCl4 administrations, the nuclear translocation of β-catenin was observed only in the non-parenchymal cells in the liver. PRI-724 treatment reduced the fibrosis induced by CCl4 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(low) CD11b(+) macrophages was induced by CCl4 and was sustained for two weeks thereafter, even after having stopped CCl4 treatment. PRI-724 accelerated the resolution of CCl4-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/β-catenin interaction may become a new therapeutic strategy in treating liver fibrosis.
Keywords: BDL, bile duct ligation; Beta-catenin; CBP, CREB-binding protein; CCL, c–c motif ligand; CCl4, carbon tetrachloride; CREB, cAMP-response element-binding protein; CXCL, c–x–c motif ligand; Fibrosis; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HCV, hepatitis C virus; HSC, hepatic stellate cell; Hepatic stellate cell; H–E, hematoxylin and eosin; Liver; MMP, matrix metalloproteinase; Macrophage; PBDL, partial BDL; SPARC, secreted protein acidic and rich in cysteine; TGF-β, transforming growth factor; TIMP-1, tissue inhibitor of metalloproteinase; αSMA, α-smooth muscle actin,.