FXR ligands protect against hepatocellular inflammation via SOCS3 induction.

Abstract

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-α 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.

• Authors: Zhizhen Xu, Gang Huang, Wei Gong, Peng Zhou, Yuanyin Zhao, Yan Zhang, Yijun Zeng, Min Gao, Zhisheng Pan, Fengtian He
• Journal: Cellular signalling (Cell Signal) Vol. 24 Issue 8 Pg. 1658-64 (Aug 2012) ISSN: 1873-3913 [Electronic] England
• PMID: 22560881 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Ligands
• Lipopolysaccharides
• Receptors, Cytoplasmic and Nuclear
• Socs3 protein, mouse
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins
• farnesoid X-activated receptor
• Chenodeoxycholic Acid

Topics

• Animals
• Carcinoma, Hepatocellular (drug therapy, immunology, pathology)
• Cells, Cultured
• Chenodeoxycholic Acid (pharmacology)
• Hep G2 Cells
• Humans
• Inflammation (drug therapy, immunology)
• Ligands
• Lipopolysaccharides (antagonists & inhibitors, pharmacology)
• Liver Neoplasms (drug therapy, immunology, pathology)
• Mice
• Mice, Inbred C57BL
• Receptors, Cytoplasmic and Nuclear (agonists, immunology)
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins (genetics, immunology)