title: Stat3 signaling activation crosslinking of TGF-β1 in hepatic stellate cell exacerbates liver injury and fibrosis.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, China.
authors.forename: Ming-Yi
authors.initials: MY
authors.lastname: Xu
authors.affiliation: Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, China.
authors.forename: Jun-Jie
authors.initials: JJ
authors.lastname: Hu
authors.affiliation: Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, China.
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, China.
authors.forename: Qing-Qing
authors.initials: QQ
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Qu
authors.affiliation: Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, China. Electronic address: lungenlu1965@163.com.
authors.forename: Lun-Gen
authors.initials: LG
authors.lastname: Lu
keywords: Hepatic stellate cell; Liver fibrosis; Signal transducer and activator of transcription 3; Transforming growth factor-β1