Statin pretreatment inhibits the LPS-induced EMT via the downregulation of TLR4 and NF-kappaB in human biliary epithelial cells.

  • Kim Y
  • Lee E
  • Jang H
 et al. 
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Abstract

BACKGROUND AND AIM: Epithelial-mesenchymal transition (EMT) of biliary epithelial cells (BECs) plays an important role in biliary fibrosis. This study investigated the effects of simvastatin on the lipopolysaccharide (LPS)-induced EMT and related signal pathways in BECs. METHODS: BECs were exposed to LPS (2 microg/mL) or TGF-beta1 (5 ng/ml) for 5 days. The EMT was assessed by a gain of mesenchymal cell markers (vimentin, N-cadherin, slug, and twist-1) and a loss of epithelial cell markers (E-cadherin). The effects of simvastatin on the EMT induced by LPS or TGF-beta1 were determined by the changes in the levels of EMT markers and TLR4 and in the JNK, p38, and NF-kB signaling pathways. RESULTS: Compared with the BECs treated with LPS alone, co-treatment with simvastatin and LPS induced an increase in the expression of E-cadherin and decreases in the expression levels of mesenchymal cell markers. The LPS-induced TLR4 expression level was slightly decreased by co-treatment with simvastatin. LPS-induced BEC growth was markedly inhibited by co-treatment with simvastatin. Furthermore, pretreatment with simvastatin inhibited the LPS-induced EMT in BECs by downregulating NF-kappaB and JNK phosphorylation. The suppressive effects of simvastatin pretreatment on the induction of the EMT by TGF-beta1 were also demonstrated in H69 cells. CONCLUSIONS: Our results demonstrate that LPS or TGF-beta1 promote the EMT in BECs that that pretreatment with simvastatin inhibited the induced EMT by downregulating TLR4 and NF-kappaB phosphorylation. This finding suggests that simvastatin can be considered a new agent for preventing biliary fibrosis associated with the EMT of BECs.

Author-supplied keywords

  • 10.1111/jgh.13230 and biliary epithelial cells
  • TGF-1
  • epithelial-mesenchymal transition
  • lipopolysaccharide
  • simvastatin
  • toll-like receptor- 4

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Authors

  • Yangmi Kim

  • Eun Jeoung Lee

  • Hee Kyung Jang

  • Chan Hyung Kim

  • Dae-Ghon Kim

  • Joung-Ho Han

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