Chrysin ameliorates chemically induced colitis in the mouse through modulation of a PXR/NF-κB signaling pathway.

Abstract

Targeted activation of pregnane X receptor (PXR) in recent years has become a therapeutic strategy for inflammatory bowel disease. Chrysin is a naturally occurring flavonoid with anti-inflammation activity. The current study investigated the role of chrysin as a putative mouse PXR agonist in preventing experimental colitis. Pre-administration of chrysin ameliorated inflammatory symptoms in mouse models of colitis (dextran sodium sulfate- and 2,4,6-trinitrobenzene sulfonic acid-induced) and resulted in down-regulation of nuclear transcription factor κB (NF-κB) target genes (inducible NO synthase, intercellular adhesion molecule-1, monocyte chemotactic protein-1, cyclooxygenase 2, tumor necrosis factor-α, and interleukin 6) in the colon mucosa. Chrysin inhibited the phosphorylation/degradation of inhibitor κBα (IκBα), which correlated with the decrease in the activity of myeloperoxidase and the levels of tumor necrosis factor-α and interleukin 6 in the colon. Consistent with the in vivo results, chrysin blocked lipopolysaccharide -stimulated nuclear translocation of NF-κB p65 in mouse macrophage RAW264.7. Furthermore, chrysin dose-dependently activated human/mouse PXR in reporter gene assays and up-regulated xenobiotic detoxification genes in the colon mucosa, but not in the liver. Silencing of PXR by RNA interference demonstrated necessity of PXR in mediating chrysin's ability to induce xenobiotic detoxification genes and NF-κB inactivation. The repression of NF-κB transcription activity by chrysin was confirmed by in vitro PXR transduction. These findings suggest that the effect of chrysin in preventing chemically induced colitis is mediated in large part by a PXR/NF-κB pathway. The data also suggest that chrysin or chrysin-like flavonoids could be further developed as intestine-specific PXR activators.

• Authors: Wei Dou, Jingjing Zhang, Eryun Zhang, Aning Sun, Lili Ding, Guixin Chou, Zhengtao Wang, Sridhar Mani
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 345 Issue 3 Pg. 473-82 (Jun 2013) ISSN: 1521-0103 [Electronic] United States
• PMID: 23536316 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Flavonoids
• Interleukin-6
• NF-kappa B
• Pregnane X Receptor
• Receptors, Steroid
• Tumor Necrosis Factor-alpha
• chrysin
• RNA
• Trinitrobenzenesulfonic Acid
• Dextran Sulfate
• Peroxidase

Topics

• Animals
• Blotting, Western
• Colitis (chemically induced, drug therapy, pathology)
• Dextran Sulfate
• Female
• Flavonoids (pharmacology)
• Fluorescent Antibody Technique
• Gene Silencing (drug effects, physiology)
• Genes, Reporter (drug effects)
• Humans
• Interleukin-6 (metabolism)
• Mice
• Mice, Inbred C57BL
• NF-kappa B (antagonists & inhibitors, drug effects)
• Peroxidase (metabolism)
• Pregnane X Receptor
• RNA (biosynthesis, isolation & purification)
• Receptors, Steroid (antagonists & inhibitors, drug effects)
• Signal Transduction (drug effects)
• Trinitrobenzenesulfonic Acid
• Tumor Necrosis Factor-alpha (metabolism)
• Up-Regulation (drug effects)