Modulation of pregnane X receptor-and electrophile responsive element-mediated gene expression by dietary polyphenolic compounds

Kluth, Dirk; Banning, Antje; Paur, Ingvild; Blomhoff, Rune; Brigelius‐Flohé, Regina

doi:10.1016/j.freeradbiomed.2006.09.028

Cited by 104 publications

(69 citation statements)

References 75 publications

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“…Interestingly, in their initial report, Ma et al (2005) used curcumin to selectively inhibit NFkB, an approach that abrogated TNFa-induced MLCK expression and barrier disruption. Curcumin has been reported to activate the PXR, an effect thought to contribute to its anti-inflammatory activity in the gastrointestinal tract (Kluth et al, 2007;Nones et al, 2009). Taken together, these data suggest that the PXR can afford barrier protection, in part, by attenuating NFkB-dependent cytokine-induced expression of MLCK.…”

Section: Discussionmentioning

confidence: 77%

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

Garg¹,

Zhao²,

Erickson³

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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The inflammatory bowel diseases (IBDs) are chronic inflammatory disorders with a complex etiology. IBD is thought to arise in genetically susceptible individuals in the context of aberrant interactions with the intestinal microbiota and other environmental risk factors. Recently, the pregnane X receptor (PXR) was identified as a sensor for microbial metabolites, whose activation can regulate the intestinal epithelial barrier. Mutations in NR1I2, the gene that encodes the PXR, have been linked to IBD, and in animal models, PXR deletion leads to barrier dysfunction. In the current study, we sought to assess the mechanism(s) through which the PXR regulates barrier function during inflammation. In Caco-2 intestinal epithelial cell monolayers, tumor necrosis factor-a/interferon-g exposure disrupted the barrier and triggered zonula occludens-1 relocalization, increased expression of myosin light-chain kinase (MLCK), and activation of c-Jun N-terminal kinase 1/2 (JNK1/2).Activation of the PXR [rifaximin and [[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenylidene]bis-phosphonic acid tetraethyl ester (SR12813); 10 mM] protected the barrier, an effect that was associated with attenuated MLCK expression and JNK1/2 activation. In vivo, activation of the PXR [pregnenolone 16a-carbonitrile (PCN)] attenuated barrier disruption induced by toll-like receptor 4 activation in wild-type, but not Pxr2/2, mice. Furthermore, PCN treatment protected the barrier in the dextran-sulfate sodium model of experimental colitis, an effect that was associated with reduced expression of mucosal MLCK and phosphorylated JNK1/2. Together, our data suggest that the PXR regulates the intestinal epithelial barrier during inflammation by modulating cytokineinduced MLCK expression and JNK1/2 activation. Thus, targeting the PXR may prove beneficial for the treatment of inflammationassociated barrier disruption in the context of IBD.

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Section: Discussionmentioning

confidence: 77%

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

Garg¹,

Zhao²,

Erickson³

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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“…In human hepatocytes, quercetin is able to attenuate ethanolinduced oxidative damage by HO-1 induction via p38 and, especially, via ERK/Nrf2 transduction pathway [13,14] . Recently, in the same cellular model, Kluth et al [15] have confirmed that quercetin is able to activate the gene expression regulated by the EpRE of HO-1, although its ability was about 10 times less than that of thyme.…”

Section: Flavonoidsmentioning

confidence: 92%

Natural heme oxygenase-1 inducers in hepatobiliary function

Volti¹,

Sacerdoti²,

Giacomo³

et al. 2008

WJG

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“…The skin benefits of PPs have been traditionally attributed to their chain-breaking antioxidant or free radical scavenging activities (6,14). However, evidence from numerous in vitro skin cell studies suggests that PPs can influence cellular functions by multiple other mechanisms, such as interaction with several receptors, modulation of signal transduction and transcription of a number of genes, post-translational modulation of enzymatic activities (9,12,16,18,19,31,33,36,40), and epigenetic regulation of gene expression (42). Although most of these functions are redox-dependent, their modulation does not compulsory depend on direct antioxidant/free radical scavenging/metal chelating properties of PPs (15,18).…”

mentioning

confidence: 99%

Plant Polyphenols Regulate Chemokine Expression and Tissue Repair in Human Keratinocytes Through Interaction with Cytoplasmic and Nuclear Components of Epidermal Growth Factor Receptor System

Pastore

Lulli

Fidanza

et al. 2012

Antioxidants & Redox Signaling

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Aims: To evaluate mechanisms underlying modulation of inflammatory chemokines in primary human keratinocytes (normal human epidermal keratinocytes) and repair-related processes in wound models by plant polyphenols (PPs) with antioxidant and superoxide scavenging properties (verbascoside [Vb], resveratrol [Rv], polydatin [Pd], quercetin [Qr], and rutin). Results: Epidermal growth factor receptor (EGFR)-controlled chemokines CXCL8/interleukin 8 (IL-8), CCL2/monocyte chemotactic protein-1 (MCP-1), and CXCL10/interferon gamma-produced protein of 10 kDa (IP-10) were modulated by transforming growth factor alpha (TGF-a) and by the tumor necrosis factor alpha/interferon gamma combination (T/I). EGFR phosphorylation, nuclear translocation, and downstream cytoplasmic signaling pathways (extracellular regulation kinase [ERK]1/2, p38, STAT3, and PI-3K) were studied. All PPs did not affect TGF-a-induced STAT3 phosphorylation, whereas they suppressed T/I-activated NFkappaB and constitutive and T/I-induced but not TGF-a-induced ERK1/2 phosphorylation. Vb and Qr suppressed total EGFR phosphorylation, but they synergized with TGF-a to enhance nuclear accumulation of phosphorylated EGFR. Vb strongly inhibited TGF-a-induced p38 phosphorylation and T/I-induced NFkappaB and activator protein-1 (AP-1) binding to DNA. Vb was an effective inhibitor of T/I-stimulated chemokine synthesis, and it accelerated scratch wound healing in vitro. Anti-inflammatory and wound healing activities of Vb were confirmed in vivo in the full-thickness excision wound. Although Pd and Rv did not affect EGFR activation/translocation, they and Qr synergized with TGF-a and T/I in the induction of IL-8 transcription/synthesis while opposing enhanced MCP-1 and IP-10 transcription/synthesis connected with pharmacologically impaired EGFR functioning. Innovation: PPs perturb the EGFR system in human keratinocytes, and this effect may be implicated in the regulation of inflammatory and repair-related processes in the skin. Conclusion: Anti-inflammatory and wound healing effects of PPs depend on their interaction with EGFR-controlled cytoplasmic and nuclear pathways rather than on their direct redox properties. Antioxid. Redox Signal. 16, 314-328.

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Modulation of pregnane X receptor-and electrophile responsive element-mediated gene expression by dietary polyphenolic compounds

Cited by 104 publications

References 75 publications

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

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

Natural heme oxygenase-1 inducers in hepatobiliary function

Plant Polyphenols Regulate Chemokine Expression and Tissue Repair in Human Keratinocytes Through Interaction with Cytoplasmic and Nuclear Components of Epidermal Growth Factor Receptor System

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