Abstract
Pregnane X receptor (PXR) expression was shown to be protective in inflammatory bowel disease (IBD). However, the mechanism by which PXR provides protection remains unclear. Wild-type and Pxr-null mice were treated with the PXR agonist pregnenolone-16alpha-carbonitrile or vehicle and administered 2.5% dextran sulfate sodium (DSS) in drinking water to induce IBD. Typical clinical symptoms were evaluated on a daily basis. In vivo intestinal permeability assays and proinflammatory cytokine analysis were performed. PXR agonist-treated mice were protected from DSS-induced colitis compared with vehicle-treated mice, as defined by body weight loss, diarrhea, rectal bleeding, colon length, and histology. Pregnenolone-16alpha-carbonitrile did not decrease the severity of IBD in Pxr-null mice. PXR agonist treatment did not increase epithelial barrier function but did decrease mRNA expression of several NF-kappaB target genes in a PXR-dependent manner. The present study clearly demonstrates a protective role for PXR agonist in DSS-induced IBD. The data suggest that PXR-mediated repression of NF-kappaB target genes in the colon is a critical mechanism by which PXR activation decreases the susceptibility of mice to DSS-induced IBD.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP-Binding Cassette Transporters / biosynthesis
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ATP-Binding Cassette Transporters / genetics
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Animals
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Colitis / chemically induced
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Colitis / genetics
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Colitis / metabolism
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Colitis / prevention & control*
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Colon / drug effects
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Colon / metabolism
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Colon / pathology
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Cytokines / genetics
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Cytokines / metabolism
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Cytoprotection / drug effects
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Dextran Sulfate
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Disease Models, Animal
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Gastrointestinal Agents / pharmacology*
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Gastrointestinal Agents / therapeutic use
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Gene Expression / drug effects
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Glutathione Transferase / biosynthesis
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Glutathione Transferase / genetics
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HCT116 Cells
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Humans
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Inflammatory Bowel Diseases / chemically induced
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Inflammatory Bowel Diseases / genetics
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Inflammatory Bowel Diseases / metabolism
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Inflammatory Bowel Diseases / prevention & control*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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NF-kappa B / antagonists & inhibitors*
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NF-kappa B / genetics
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NF-kappa B / metabolism*
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Pregnane X Receptor
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Pregnenolone Carbonitrile / pharmacology*
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Pregnenolone Carbonitrile / therapeutic use
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RNA, Messenger / metabolism
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Receptors, Steroid / agonists*
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Receptors, Steroid / deficiency
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Receptors, Steroid / genetics
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Receptors, Steroid / metabolism
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Repressor Proteins / agonists
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Repressor Proteins / metabolism
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Severity of Illness Index
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Time Factors
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Transfection
Substances
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ATP-Binding Cassette Transporters
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Cytokines
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Gastrointestinal Agents
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NF-kappa B
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Pregnane X Receptor
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RNA, Messenger
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Receptors, Steroid
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Repressor Proteins
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Pregnenolone Carbonitrile
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Dextran Sulfate
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Glutathione Transferase