Inhibition of transforming growth factor-β-induced liver fibrosis by a retinoic acid derivative via the suppression of Col 1A2 promoter activity

• Published in: Biochemical and biophysical research communications 2008-08, Vol.373 (2), p.219-223
• Main Authors: Yang, Kun-Lin, Chang, Wen-Teng, Hung, Kuo-Chen, Li, Eric I.C., Chuang, Chia-Chang
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Collagen - antagonists & inhibitors; Collagen - genetics; Collagen Type I; Cyclohexanes - pharmacology; Cytosol - metabolism; Gene Expression - drug effects; Hepatic stellate cells; Humans; Hydrodynamics-based gene delivery; Liver Cirrhosis - chemically induced; Liver Cirrhosis - prevention & control; Liver fibrosis; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Pentanoic Acids - pharmacology; Phellinus linteus; Phosphorylation; Promoter Regions, Genetic - drug effects; Reactive Oxygen Species - antagonists & inhibitors; Reactive Oxygen Species - metabolism; Smad family; Smad Proteins - metabolism; Sp1 binding activity; Sp1 Transcription Factor - antagonists & inhibitors; Sp1 Transcription Factor - metabolism; TGF-β; Transforming Growth Factor beta - antagonists & inhibitors; Transforming Growth Factor beta - pharmacology; Tretinoin - pharmacology
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2008.05.192

Transforming growth factor-beta1 (TGF-β1) mediates expression of collagen 1A2 (Col 1A2) gene via a synergistic cooperation between Smad2/Smad3 and Sp1, both act on the Col 1A2 gene promoter. In our previous study, we reported that a retinoic acid derivative obtained from Phellinus linteus (designated PL) antagonizes TGF-β-induced liver fibrosis through regulation of ROS and calcium influx. In this continuing study we seek further the effect of PL on the Smad signaling pathway. We used a Col 1A2 promoter-luciferase construct to study the action of PL on Smad through TGF-β. We found that PL decreases the promoter activity of Col 1A2, hinders the translocalization of phosphorylated Smad2/3–Smad 4 complex from cytosol into nucleus and inhibits Sp1 binding activity. These results suggest that PL inhibits TGF-β1-induced Col 1A2 promoter activity through blocking ROS and calcium influx as well as impeding Sp1 binding and translocalization of pSmad 2/3–Smad4 complex into nucleus.