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

Aditya Garg, Angela Zhao, Sarah L. Erickson, Subhajit Mukherjee, Aik Jiang Lau, Laurie Alston, Thomas K H Chang, Sridhar Mani, Simon A. Hirota

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)91-101
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume359
Issue number1
DOIs
StatePublished - Oct 1 2016

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Pregnanes
Myosin-Light-Chain Kinase
Phosphotransferases
Cytokines
Inflammation
Inflammatory Bowel Diseases
Pregnenolone Carbonitrile
rifaximin
Mitogen-Activated Protein Kinase 9
Mitogen-Activated Protein Kinase 8
Organophosphonates
Dextran Sulfate
Toll-Like Receptor 4
pregnane X receptor
Tight Junctions
Colitis
Interferons
Theoretical Models
Animal Models
Tumor Necrosis Factor-alpha

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

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. / Garg, Aditya; Zhao, Angela; Erickson, Sarah L.; Mukherjee, Subhajit; Lau, Aik Jiang; Alston, Laurie; Chang, Thomas K H; Mani, Sridhar; Hirota, Simon A.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 359, No. 1, 01.10.2016, p. 91-101.

Research output: Contribution to journalArticle

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abstract = "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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AU - Zhao, Angela

AU - Erickson, Sarah L.

AU - Mukherjee, Subhajit

AU - Lau, Aik Jiang

AU - Alston, Laurie

AU - Chang, Thomas K H

AU - Mani, Sridhar

AU - Hirota, Simon A.

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