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
Open accessAbstract
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-α/interferon-γ 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 μM] protected the barrier, an effect that was associated with attenuated MLCK expression and JNK1/2 activation. In vivo, activation of the PXR [pregnenolone 16α-carbonitrile (PCN)] attenuated barrier disruption induced by toll-like receptor 4 activation in wild-type, but not Pxr-/-, 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 cytokine-induced MLCK expression and JNK1/2 activation. Thus, targeting the PXR may prove beneficial for the treatment of inflammation-associated barrier disruption in the context of IBD.
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Nr1i2−/− mice exhibit impaired epithelial barrier function.
“Nr1i2−/− mice exhibit impaired epithelial barrier function”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Garg et al., 2016
Synthetic NR1I2 agonists exert protective effects in mouse models of colitis.
“administration of synthetic NR1I2 agonists exerts protective effects in mouse models of colitis (Dou et al., 2013; Garg et al., 2016; Shah et al., 2007; Terc et al., 2014; Venkatesh et al., 2014).”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Garg et al., 2016
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- Authors
- Garg, A., Zhao, A., Erickson, S. L., Mukherjee, S., Lau, A. J., Alston, L., Chang, T. K. H., Mani, S., & Hirota, S. A.
- Affiliations
- Albert Einstein College of Medicine (US)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2016-10
- Volume
- 359
- Issue
- 1
- Pages
- 91-101
- ISSN
- 0022-3565 (ISSN-L)
- PMC
- PMC5034705
- OpenAlex
- W2500169107
- Cited by
- 82
- References
- 71
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 10 · 2023: 10 · 2022: 8 · 2021: 15 · 2020: 4 · 2019: 9 · 2018: 7 · 2017: 6
- FWCI
- 5.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Crohn's and Colitis Foundation (362520)
- National Institutes of Health (UL1TR001073)
- Canadian Institutes of Health Research
- National Cancer Institute (R01CA161879, R01CA127231, P30CA013330)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- pregnane X receptor, intestinal epithelial barrier, barrier dysfunction, inflammatory bowel disease, myosin light chain kinase, c-Jun N-terminal kinase, zonula occludens-1, TLR4, DSS-induced colitis, pregnenolone-16α-carbonitrile, rifaximin, intestinal inflammation
- MeSH terms
- Pregnane X Receptor, Animals, Colitis, Enzyme Activation, Humans, Inflammation, Interferon-gamma, Intestinal Mucosa, Male, Myosin-Light-Chain Kinase, Receptors, Steroid, Tumor Necrosis Factor-alpha, Signal Transduction, Gene Expression Regulation, Enzymologic, Cytokines, Dextran Sulfate, NF-kappa B, Caco-2 Cells, Mitogen-Activated Protein Kinase 8, Mitogen-Activated Protein Kinase 9, Toll-Like Receptor 4, Mice, Hep G2 Cells
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