Pregnane X receptor (PXR/NR1I2) gene haplotypes modulate susceptibility to inflammatory bowel disease

Glas, Jürgen; Seiderer, Julia; Fischer, D; Tengler, Barbara; Pfennig, Simone; Wetzke, Martin; Beigel, Florian; Olszak, Torsten; Weidinger, Maria; Göke, Burkhard; Ochsenkühn, Thomas; Folwaczny, Matthias; Müller‐Myhsok, Bertram; Diegelmann, Julia; Czamara, Darina; Brand, Stephan

doi:10.1002/ibd.21562

Cited by 32 publications

(29 citation statements)

References 41 publications

(47 reference statements)

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“…Our study may provide insight into how PXR dysfunction may contribute to IBD susceptibility (Langmann et al, 2004;Dring et al, 2006;Martinez et al, 2007;Glas et al, 2011). Whereas others have characterized the anti-inflammatory effects of PXR signaling in the gut, our in vitro and in vivo data suggest that selective activation of the PXR affords protection of the intestinal epithelial barrier in the context of inflammation.…”

Section: Discussionmentioning

confidence: 61%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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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: 61%

Section: Introductionmentioning

confidence: 99%

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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“…These 71 susceptibility loci explain only slightly more than 20% of CD heritability. Therefore, it is assumed that a number of rare SNPs and haplotypes contribute to the overall CD risk such as recently shown by us for PXR gene variants [58]. In addition, most likely a high number of common CD risk genes with small effect size are still unidentified but for their identification very large cohorts would be required.…”

Section: Discussionmentioning

confidence: 99%

The Role of Osteopontin (OPN/SPP1) Haplotypes in the Susceptibility to Crohn's Disease

et al. 2011

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BackgroundOsteopontin represents a multifunctional molecule playing a pivotal role in chronic inflammatory and autoimmune diseases. Its expression is increased in inflammatory bowel disease (IBD). The aim of our study was to analyze the association of osteopontin (OPN/SPP1) gene variants in a large cohort of IBD patients.Methodology/Principal FindingsGenomic DNA from 2819 Caucasian individuals (n = 841 patients with Crohn's disease (CD), n = 473 patients with ulcerative colitis (UC), and n = 1505 healthy unrelated controls) was analyzed for nine OPN SNPs (rs2728127, rs2853744, rs11730582, rs11739060, rs28357094, rs4754 = p.Asp80Asp, rs1126616 = p.Ala236Ala, rs1126772 and rs9138). Considering the important role of osteopontin in Th17-mediated diseases, we performed analysis for epistasis with IBD-associated IL23R variants and analyzed serum levels of the Th17 cytokine IL-22. For four OPN SNPs (rs4754, rs1126616, rs1126772 and rs9138), we observed significantly different distributions between male and female CD patients. rs4754 was protective in male CD patients (p = 0.0004, OR = 0.69). None of the other investigated OPN SNPs was associated with CD or UC susceptibility. However, several OPN haplotypes showed significant associations with CD susceptibility. The strongest association was found for a haplotype consisting of the 8 OPN SNPs rs2728127-rs2853744-rs11730582-rs11439060-rs28357094-rs112661-rs1126772-rs9138 (omnibus p-value = 2.07×10−8). Overall, the mean IL-22 secretion in the combined group of OPN minor allele carriers with CD was significantly lower than that of CD patients with OPN wildtype alleles (p = 3.66×10−5). There was evidence for weak epistasis between the OPN SNP rs28357094 with the IL23R SNP rs10489629 (p = 4.18×10−2) and between OPN SNP rs1126616 and IL23R SNP rs2201841 (p = 4.18×10−2) but none of these associations remained significant after Bonferroni correction.Conclusions/SignificanceOur study identified OPN haplotypes as modifiers of CD susceptibility, while the combined effects of certain OPN variants may modulate IL-22 secretion.

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“…An Irish cohort including 422 patients with IBD and 350 ethnically matched controls was examined for single nucleotide polymorphisms (SNPs), and several polymorphisms were identified in the PXR gene that were over-represented in IBD patients as compared with controls 57 . Moreover, an independent study identified other SNPs in the PXR gene that were associated with CD but not with UC in Caucasian patients 58 . Evaluation of a Spanish cohort of 365 UC and 331 CD patients, and 550 ethnically matched controls showed significant differences in the overall haplotype of IBD between UC and CD patients 59 in PXR SNPs.…”

Section: Mechanisms For the Influence Of Pxr On Ibdmentioning

confidence: 99%

Pregnane X receptor as a target for treatment of inflammatory bowel disorders

Cheng

Shah

Gonzalez

2012

Trends in Pharmacological Sciences

142

125

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Pregnane X receptor (PXR; NR1I2), a member of the nuclear receptor superfamily, has a major role in the induction of genes involved in drug transport and metabolism. Recent studies in mice have provided insight into a novel function for PXR in inflammatory bowel disease (IBD). The mechanisms of the protective effect of PXR activation on IBD is not fully established, but is due in part to the attenuation of nuclear factor kappa B (NF-κB) signaling that results in lower expression of proinflammatory cytokines. Recent clinical trials with the antibiotic rifaximin, a PXR agonist in the gastrointestinal system, have revealed its potential therapeutic value in the treatment of intestinal inflammation in humans. Thus, PXR may be a novel target for IBD therapy.

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Pregnane X receptor (PXR/NR1I2) gene haplotypes modulate susceptibility to inflammatory bowel disease

Cited by 32 publications

References 41 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

The Role of Osteopontin (OPN/SPP1) Haplotypes in the Susceptibility to Crohn's Disease

Pregnane X receptor as a target for treatment of inflammatory bowel disorders

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