Ming-Yi Xu1, Jun-Jie Hu1, Jie Shen1, Mei-Ling Wang1, Qing-Qing Zhang1, Ying Qu1, Lun-Gen Lu2. 1. Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, China. 2. Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, China. Electronic address: lungenlu1965@163.com.
Abstract
BACKGROUND/AIMS: The role of signal transducer and activator of transcription 3 (Stat3) in liver fibrosis is still controversial. Since hepatic stellate cells (HSCs) and transforming growth factor-β1 (TGF-β1) are central to the fibrogenesis, our goal was to clarify the mechanism of Stat3 crosslinking of TGF-β1 signaling. METHODS: Stat3, TGF-β1 mRNA and protein expressions were examined in liver tissues of chronic hepatitis B (CHB) patients and diethylinitrosamine (DEN)-induced rat fibrosis model. The effect of Stat3 activation or suppression on TGF-β1 signaling in HSCs was tested in vitro and in vivo. RESULTS: Stat3 expression as well as TGF-β1 was increased in CHB patients and DEN-induced fibrosis rat model. This was strongly correlated with increase in fibrosis staging. TGF-β1, a mediator of fibrosis, was enhanced by Stat3, but suppressed by siRNA-mediated RNA knockdown of Stat3 (siStat3) or Janus kinase 2 inhibitor (AG490) both in vivo and in vitro. Stat3 crosslinking TGF-β1 signaling plays an important role in HSC activation and increasing fibrosis related products. TGF-β1 could not achieve profibrogenic cytokine and anti-apoptosis characteristics without Stat3 activation in HSCs. CONCLUSION: We provide a novel role of Stat3 cooperating TGF-β1 in activation and anti-apoptotic effect of HSCs. Stat3 worsens liver fibrosis through the up-regulation of TGF-β1 and fibrotic product expression.
BACKGROUND/AIMS: The role of signal transducer and activator of transcription 3 (Stat3) in liver fibrosis is still controversial. Since hepatic stellate cells (HSCs) and transforming growth factor-β1 (TGF-β1) are central to the fibrogenesis, our goal was to clarify the mechanism of Stat3 crosslinking of TGF-β1 signaling. METHODS: Stat3, TGF-β1 mRNA and protein expressions were examined in liver tissues of chronic hepatitis B (CHB) patients and diethylinitrosamine (DEN)-induced ratfibrosis model. The effect of Stat3 activation or suppression on TGF-β1 signaling in HSCs was tested in vitro and in vivo. RESULTS: Stat3 expression as well as TGF-β1 was increased in CHB patients and DEN-induced fibrosisrat model. This was strongly correlated with increase in fibrosis staging. TGF-β1, a mediator of fibrosis, was enhanced by Stat3, but suppressed by siRNA-mediated RNA knockdown of Stat3 (siStat3) or Janus kinase 2 inhibitor (AG490) both in vivo and in vitro. Stat3 crosslinking TGF-β1 signaling plays an important role in HSC activation and increasing fibrosis related products. TGF-β1 could not achieve profibrogenic cytokine and anti-apoptosis characteristics without Stat3 activation in HSCs. CONCLUSION: We provide a novel role of Stat3 cooperating TGF-β1 in activation and anti-apoptotic effect of HSCs. Stat3 worsens liver fibrosis through the up-regulation of TGF-β1 and fibrotic product expression.
Authors: Pradip B Devhare; Reina Sasaki; Shubham Shrivastava; Adrian M Di Bisceglie; Ranjit Ray; Ratna B Ray Journal: J Virol Date: 2017-02-28 Impact factor: 5.103
Authors: Raymond S Oh; Andrew J Haak; Karry M J Smith; Giovanni Ligresti; Kyoung Moo Choi; Tiao Xie; Shaohua Wang; Paula R Walters; Michael A Thompson; Michelle R Freeman; Logan J Manlove; Vivian M Chu; Carol Feghali-Bostwick; Anja C Roden; Jürgen Schymeinsky; Christina M Pabelick; Y S Prakash; Robert Vassallo; Daniel J Tschumperlin Journal: J Cell Sci Date: 2018-05-15 Impact factor: 5.285