FXR ligands protect against hepatocellular inflammation via SOCS3 induction
- 作者：Zhizhen Xu ; Gang Huang ; Wei Gong ; Peng Zhou ; Yuanyin Zhao ; Yan Zhang ; Yijun Zeng ; Min Gao ; Zhisheng Pan ; Fengtian He ; hefengtian06@yahoo.com.cn
- 关键词：FXR ; farnesoid X receptor ; CDCA ; chenodeoxycholic acid ; JAK ; Janus tyrosine kinase ; STAT ; signal transducer and activators of transcription ; IL-6 ; interleukin-6 ; TNF-伪 ; tumor necrosis factor-伪 ; ICAM-1 ; intercellular adhesion molecule-1 ; LPS ; lipopolysac
- 刊名：Cellular Signalling
- 出版年：2012
- 期刊代码：42_08986568
- 类别：bio
- 出版时间：August, 2012
- 卷：24
- 期：8
- 页码：1658-1664
- 文件大小：867 K
摘要
Because of the anti-inflammatory actions of farnesoid X receptor (FXR) agonists, FXR has received much attention as a potential therapeutic target. However, the molecular mechanisms of actions have not yet been elucidated. In the present study, we reported that in the animal model of LPS-induced liver injury, administration of the FXR natural ligand CDCA could attenuate hepatocyte inflammatory damage, reduce transaminase activities, suppress inflammation mediators (IL-6, TNF-伪 and ICAM-1) expression and inhibit STAT3 phosphorylation. These protective effects of FXR were accompanied by an increased expression of suppressor of cytokine signaling 3 (SOCS3), which is a negative feedback regulator of cytokine-STAT3 signaling. We then demonstrated that the beneficial effects of FXR agonist in STAT3 activation were weakened by small interfering RNA-mediated SOCS3 knockdown in hepacytes. Moreover we observed both natural ligand CDCA and synthetic ligand GW4064 could upregulate SOCS 3 expression by enhancing the promoter activity in hepatocytes. These results suggest modulation of SOCS3 expression may represent a novel mechanism through which FXR activation could selectively affect cytokine bioactivity in inflammation response. FXR ligands may be potentially therapeutic in the treatment of liver inflammatory diseases via SOCS3 induction.