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

Wei Dou, Jingjing Zhang, Eryun Zhang, Aning Sun, Lili Ding, Guixin Chou, Zhengtao Wang, Sridhar Mani

Research output: Contribution to journalArticle

75 Scopus citations

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 antiinflammation 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 kB (NF-kB) target genes (inducible NO synthase, intercellular adhesion molecule-1, monocyte chemotactic protein-1, cyclooxygenase 2, tumor necrosis factor-a, and interleukin 6) in the colon mucosa. Chrysin inhibited the phosphorylation/degradation of inhibitor kBa (IkBa), which correlated with the decrease in the activity of myeloperoxidase and the levels of tumor necrosis factor-a and interleukin 6 in the colon. Consistent with the in vivo results, chrysin blocked lipopolysaccharide-stimulated nuclear translocation of NF-kB 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-kB inactivation. The repression of NF-kB 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-kB pathway. The data also suggest that chrysin or chrysin-like flavonoids could be further developed as intestine-specific PXR activators.

Original languageEnglish (US)
Pages (from-to)473-482
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume345
Issue number3
DOIs
StatePublished - Jun 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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