NIM811 downregulates transforming growth factor‑β signal transduction in vivo and in vitro

Chen,Jing; Liu,Dian‑Gang; Wang,Hui; Wu,Xiao‑Ning; Cong,Min; You,Hong; Jia,Ji‑Dong

doi:10.3892/mmr.2015.4572

NIM811 downregulates transforming growth factor‑β signal transduction in vivo and in vitro

Authors:
- Jing Chen
- Dian‑Gang Liu
- Hui Wang
- Xiao‑Ning Wu
- Min Cong
- Hong You
- Ji‑Dong Jia
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Affiliations: Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China, Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, P.R. China
Published online on: November 16, 2015 https://doi.org/10.3892/mmr.2015.4572
Pages: 522-528

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Abstract

Liver fibrosis is the common histological feature of a number of chronic liver diseases, and leads to cirrhosis and hepatocellular carcinoma (HCC). It has been demonstrated that N‑methyl‑4‑isoleucine cyclosporine (NIM811) attenuates CCl4‑induced liver fibrosis and inflammation in rats. The present study investigated whether NIM811 downregulated transforming growth factor (TGF)‑β signaling in rats with CCl4‑induced liver fibrosis and in HSC‑T6 cells. Liver tissues were obtained from rats with CCl4‑induced liver fibrosis, with or without NIM811 treatment. HSC‑T6 cells were cultured with or without NIM811 for 18 h under serum‑free conditions. Expression of collagen I, α‑smooth muscle actin (α‑SMA), TGF‑β1, TGF‑β receptor I (TβR‑I) and TGF‑β pathway downstream signaling molecules were measured by reverse transcription‑quantitative polymerase chain reaction and/or western blotting. Collagen I and TGF‑β1 content in the cell supernatant was measured by ELISA. NIM811 profoundly inhibited collagen I, α‑SMA, TGF‑β1 and TβR‑I expression in the liver of CCl4‑treated rats. Phosphorylation of Smad2, 3 and 1/5/8 was decreased in the liver of NIM811‑treated groups, accompanied by increased In addition, Smad7 expression compared with the CCl4‑treated rats. NIM811 inhibited collagen I, TGF‑β1 and TβR‑I expression in HSC‑T6 cells. Smad1 mRNA and phospho‑Smad1/5/8 protein levels decreased following NIM811 treatment, accompanied by increased Smad7 expression in HSC‑T6 cells compared with normal controls. Furthermore, NIM811 also inhibited collagen I mRNA expression in the liver of rats with CCl4‑induced liver fibrosis and in HSC‑T6 cells. The results suggest that the antifibrotic effect of NIM811 was due to the inhibition of TGF‑β1 and its downstream signaling molecules.

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