Activation of farnesoid X receptor increases the expression of cytokine inducible SH2-containing protein in HepG2 cells.

Abstract

Cytokine inducible SH2-containing protein (CISH), which negatively regulates cytokine signaling by inhibiting JAK2/STAT5 activity, is regarded as a therapeutic target for inflammatory diseases. Farnesoid X receptor (FXR), a ligand-activated transcription factor, has been proposed to play a protective function in the inflammatory responses. However, the role of FXR in modulation of CISH expression is unknown. In the present study, we for the first time identified that in human hepatoma cell line HepG2 the activation of FXR by the natural agonist chenodeoxycholic acid (CDCA) and the synthetic specific agonist GW4064 upregulated CISH at both transcriptional and translational levels, and inhibited interleukin (IL)6-induced STAT5 activation. Moreover, the in vivo experiment demonstrated that gavaging mice with CDCA increased CISH expression and reduced basal STAT5 phosphorylation in liver tissues. Reporter assay showed that FXR agonists enhanced the transcriptional activity of CISH promoter. These data suggest that FXR may serve as a novel molecular target for manipulating CISH expression in hepatocytes. FXR-mediated upregulation of CISH may play an important role in the homeostasis of cytokine signal networks and be beneficial to control cytokine-associated inflammatory diseases.

• Authors: Zhizhen Xu, Gang Huang, Wei Gong, Yuanyin Zhao, Peng Zhou, Yijun Zeng, Fengtian He
• Journal: Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research (J Interferon Cytokine Res) Vol. 32 Issue 11 Pg. 517-23 (Nov 2012) ISSN: 1557-7465 [Electronic] United States
• PMID: 22817871 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Interleukin-6
• Isoxazoles
• Receptors, Cytoplasmic and Nuclear
• STAT5 Transcription Factor
• Suppressor of Cytokine Signaling Proteins
• cytokine inducible SH2-containing protein
• farnesoid X-activated receptor
• Chenodeoxycholic Acid
• Jak2 protein, mouse
• Janus Kinase 2
• GW 4064

Topics

• Animals
• Chenodeoxycholic Acid (metabolism, pharmacology)
• Cytokines (antagonists & inhibitors, metabolism)
• Hep G2 Cells
• Hepatocytes (drug effects, metabolism)
• Humans
• Interleukin-6 (antagonists & inhibitors)
• Isoxazoles (pharmacology)
• Janus Kinase 2 (antagonists & inhibitors)
• Liver (drug effects, metabolism)
• Mice
• Mice, Inbred C57BL
• Phosphorylation
• Protein Biosynthesis (drug effects)
• Receptors, Cytoplasmic and Nuclear (metabolism)
• STAT5 Transcription Factor (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)
• Suppressor of Cytokine Signaling Proteins (metabolism)
• Transcription, Genetic (drug effects)
• Transcriptional Activation
• Up-Regulation