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 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.

Pregnane X Receptor Activation Attenuates Inflammation-Associated Intestinal Epithelial Barrier Dysfunction by Inhibiting Cytokine-Induced Myosin Light-Chain Kinase Expression and c-Jun N-Terminal Kinase 1/2 Activation

“…We, and others, have reported previously that the PXR plays an important role in maintaining intestinal mucosal homeostasis (Zhou et al, 2006;Terc et al, 2014;Venkatesh et al, 2014), and its activation dampens inflammation and mucosal damage in experimental colitis Shah et al, 2007;Dou et al, 2012Dou et al, , 2013Dou et al, , 2014Terc et al, 2014). In our previous report, we found that treating mice with PCN attenuated colonic mucosal neutrophil infiltration and afforded barrier protection (Terc et al, 2014).…”

“…Highly expressed in the liver and intestinal epithelium, the PXR has been previously characterized as a master regulator of xenobiotic metabolism and clearance (Watkins et al, 2002;Staudinger et al, 2006;Shukla et al, 2011;Dou et al, 2013;Pondugula and Mani, 2013). Acting as a sensor of exogenous chemicals, the PXR's activation leads to the expression of a variety of target genes related to detoxification and efflux pathways.…”

“…Interestingly, genetic studies have identified single-nucleotide polymorphisms in NR1I2, the gene that encodes the PXR, which are associated with increased susceptibility for developing Crohn's disease and ulcerative colitis (Langmann et al, 2004;Dring et al, 2006;Martinez et al, 2007;Glas et al, 2011). Furthermore, others have reported that selective activation of the PXR attenuates nuclear factor k-light-chain-enhancer of activated B cells (NFkB)-dependent inflammatory signaling in the intestinal epithelium Mencarelli et al, 2010Mencarelli et al, , 2011, an effect associated with protection in experimental models of colitis Shah et al, 2007;Dou et al, 2012Dou et al, , 2013Terc et al, 2014). In the current study, we sought to assess whether stimulation of the PXR in IECs regulates the intracellular signaling pathways that modulate barrier function in the context of inflammation.…”

Paeoniflorin abrogates DSS-induced colitis via a TLR4-dependent pathway

“…Following measurement of the colon length, the distal colon was taken and fixed in 10% (wt/vol) buffered formalin for H&E staining. Histological damage was assessed as a combined score of inflammatory cell infiltration (score 0 -3) and mucosal damage (score 0 -3) by a method previously described (5,24,36). For inflammatory cell infiltration in the colon mucosa, rare inflammatory cells (mononuclear infiltrates) in the lamina propria were counted as 0; increased numbers of inflammatory cells, including neutrophils in the lamina propria, were counted as 1; confluence of inflammatory cells, extending into the submucosa, were scored as 2; and a score of 3 was given for transmural extension of the inflammatory cell infiltration.…”

Notoginsenoside R1 Attenuates Experimental Inflammatory Bowel Disease via Pregnane X Receptor Activation

“…DSS or trinitrobenzene sulfonic acid (TNBS) colitis was induced in mice as described previously (Dou et al, 2012(Dou et al, , 2013b. In brief, 4% (w/v) DSS (molecular mass 36-50 kDa; MP Biomedicals, Solon, OH) was administered in the drinking water (tap water) for 7 days, whereas control mice received tap water only (n 5 10 mice in each group).…”