Stat3 signaling activation crosslinking of TGF-ß1 in hepatic stellate cell exacerbates liver injury and fibrosis.
Biochim Biophys Acta
; 1842(11): 2237-45, 2014 Nov.
Article
em En
| MEDLINE
| ID: mdl-25092172
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-ß1 (TGF-ß1) are central to the fibrogenesis, our goal was to clarify the mechanism of Stat3 crosslinking of TGF-ß1 signaling.METHODS:
Stat3, TGF-ß1 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-ß1 signaling in HSCs was tested in vitro and in vivo.RESULTS:
Stat3 expression as well as TGF-ß1 was increased in CHB patients and DEN-induced fibrosis rat model. This was strongly correlated with increase in fibrosis staging. TGF-ß1, 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-ß1 signaling plays an important role in HSC activation and increasing fibrosis related products. TGF-ß1 could not achieve profibrogenic cytokine and anti-apoptosis characteristics without Stat3 activation in HSCs.CONCLUSION:
We provide a novel role of Stat3 cooperating TGF-ß1 in activation and anti-apoptotic effect of HSCs. Stat3 worsens liver fibrosis through the up-regulation of TGF-ß1 and fibrotic product expression.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Tipo de estudo:
Prognostic_studies
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article