Quercetin Inhibits TNF-Induced NF-κB Transcription Factor Recruitment to Proinflammatory Gene Promoters in Murine Intestinal Epithelial Cells

Abstract

Flavonoids may play an important role for adjunct nutritional therapy of chronic intestinal inflammation. In this study, we characterized the molecular mechanisms by which quercetin and its enteric bacterial metabolites, taxifolin, alphitonin, and 3, 4-dihydroxy-phenylacetic acid, inhibit tumor necrosis factor alpha (TNF)-induced proinflammatory gene expression in the murine small intestinal epithelial cell (IEC) line Mode-K as well as in heterozygous TNFDeltaARE/WT mice, a murine model of experimental ileitis. Quercetin inhibited TNF-induced interferon-gamma-inducible protein 10 (IP-10) and macrophage inflammatory protein 2 (MIP-2) gene expression in Mode-K cells with effective inhibitory concentration of 40 and 44 micromol/L, respectively. Interestingly, taxifolin, alphitonin, and 3,4-dihydroxy-phenylacetic acid did not inhibit TNF responses in IEC, suggesting that microbial transformation of quercetin completely abolished its anti-inflammatory effect. At the molecular level, quercetin inhibited Akt phosphorylation but did not inhibit TNF-induced RelA/I-kappaB phosphorylation and IkappaB degradation or TNF-alpha-induced nuclear factor-kappaB transcriptional activity. Most important for understanding the mechanism involved, chromatin immunoprecipitation analysis revealed inhibitory effects of quercetin on phospho-RelA recruitment to the IP-10 and MIP-2 gene promoters. In addition, and consistent with the lack of cAMP response element binding protein (CBP)/p300 recruitment and phosphorylation/acetylation of histone 3 at the promoter binding site, quercetin inhibited histone acetyl transferase activity. The oral application of quercetin to heterozygous TNFDeltaARE/WT mice [10 mg/(d x kg body wt)] significantly inhibited IP-10 and MIP-2 gene expression in primary ileal epithelial cells but did not affect tissue pathology. These studies support an anti-inflammatory effect of quercetin in epithelial cells through mechanisms that inhibit cofactor recruitment at the chromatin of proinflammatory genes.

Plant Phytochemicals as Epigenetic Modulators: Role in Cancer Chemoprevention

“…It inhibited the growth of colon cancer RKO cells by reversing the silencing of hypermethylated p16INK4a gene by demethylating its promoter (96). Quercetin treatment inhibited the expression of TNF-induced interferon-gamma-inducible protein 10 [IP-10] and macrophage inflammatory protein 2 [MIP-2] by inhibiting the activity of CBP/p300 and phosphorylation/acetylation of histone H3 on the promoter region of these genes (97). Quercetin treatment in human leukemia HL-60 cells induced FasLmediated extrinsic apoptosis pathway through caspase-8 activation, Bid cleavage, changes in conformation of Bax and cytochrome c release.…”

Quercetin exerts a neuroprotective effect through inhibition of the iNOS/NO system and pro-inflammation gene expression in PC12 cells and in zebrafish

“…Quercetin, which is one of the most common naturally occurring flavonoids, has been shown to possess diverse biological activities, including anti-tumoral, anti-thrombotic, anti-inflammatory and anti-apoptotic effects (9)(10)(11)(12). Although quercetin and structurally related flavonoids have been shown to have a neuroprotective capacity in various in vitro and in vivo experimental models (13)(14)(15)(16), the neuroprotective (17).…”

Total Glucosides of <i>Paeonia lactiflora</i> Pall Suppress Nitric Oxide Production and iNOS Expression in Lipopolysaccharide-Stimulated RAW264.7 Macrophages

“…In the resting state, NF-κB binds to IκB proteins and delays in the cytoplasm [17]. Stimulating factors including LPS and cytokines [9,10] can induce the degradation of IκB proteins, resulting in the nuclear translocation of NF-κB, where NF-κB can promote the transcription of pro-inflammatory genes. In this study, we investigated the effect and mechanism of TGPL on NF-κB activation.…”

“…NF-κB is present in the cytoplasm in an quiescent state, complexed with the inhibitory κB (IκB) proteins including IκBα, IκBβ, IκBε, p105 and p100 [8]. Lipopolysaccharide (LPS) [9] or cytokines [10] can trigger NF-κB activation through induced IκB degradation, which resulting in the release and nuclear translocation of p65. In the nucleus, p65 binds to the promoter regions of a number of inflammatory genes including iNOS for transcriptional regulation.…”