Stat3 signaling activation crosslinking of TGF-β1 in hepatic stellate cell exacerbates liver injury and fibrosis

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-beta 1 (TGF-beta 1) are central to the fibrogenesis, our goal was to clarify the mechanism of Stat3 crosslinking of TGF-beta 1 signaling. Methods: Stat3, TGF-beta 1 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-beta 1 signaling in HSCs was tested in vitro and in vivo. Results: Stat3 expression as well as TGF-beta 1 was increased in CHB patients and DEN-induced fibrosis rat model. This was strongly correlated with increase in fibrosis staging. TGF-beta 1, 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-beta 1 signaling plays an important role in HSC activation and increasing fibrosis related products. TGF-beta 1 could not achieve profibrogenic cytokine and anti-apoptosis characteristics without Stat3 activation in HSCs. Conclusion: We provide a novel role of Stat3 cooperating TGF-beta 1 in activation and anti-apoptotic effect of HSCs. Stat3 worsens liver fibrosis through the up-regulation of TGF-beta 1 and fibrotic product expression. (C) 2014 Elsevier B.V. All rights reserved.