Interaction between insulin-like growth factor binding protein-related protein 1 and trans-forming growth factor beta 1 in primary hepatic stellate cells

摘要

BACKGROUND: We previously showed that insulin-like growth factor binding protein-related protein 1 (IGFBPrP1) is a novel mediator in liver fibrosis. Transforming growth factor beta 1 (TGFβ1) is known as the strongest effector of liver fi-brosis. Therefore, we aimed to investigate the detailed interac-tion between IGFBPrP1 and TGFβ1 in primary hepatic stellate cells (HSCs). METHODS: We overexpressed TGFβ1 or IGFBPrP1 and in-hibited TGFβ1 expression in primary HSCs for 6, 12, 24, 48, 72, and 96 hours to investigate their interaction and observe the accompanying expressions of α-smooth muscle actin (α-SMA), collagen I, fibronectin, and phosphorylated-mothers against decapentaplegic homolog 2/3 (p-Smad2/3). RESULTS: We found that the adenovirus vector encoding the TGFβ1 gene (AdTGFβ1) induced IGFBPrP1 expression while that of α-SMA, collagen I, fibronectin, and TGFβ1 increased gradually. Concomitantly, AdIGFBPrP1 upregulated TGFβ1, α-SMA, collagen I, fibronectin, and p-Smad2/3 in a time-de-pendent manner while IGFBPrP1 expression was decreased at 96 hours. Inhibition of TGFβ1 expression reduced the IGFB-PrP1-stimulated expression of α-SMA, collagen I, fibronectin, and p-Smad2/3. CONCLUSIONS: These findings for the first time suggest the existence of a possible mutually regulation between IGFBPrP1 and TGFβ1, which likely accelerates liver fibrosis progression. Furthermore, IGFBPrP1 likely participates in liver fibrosis in a TGFβ1-depedent manner, and may act as an upstream regu-latory factor of TGFβ1 in the Smad pathway.