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Am J Physiol Gastrointest Liver Physiol (December 14, 2006). doi:10.1152/ajpgi.00528.2006
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Submitted on November 11, 2006
Accepted on December 14, 2006

Pregnane X Receptor Activation Ameliorates DSS-Induced IBD Via Inhibition of NF{kappa}B Target Gene Expression

Yatrik Shah1, Xiaochao Ma1, Keiichirou Morimura1, Insook Kim1, and Frank J. Gonzalez2*

1 Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland, United States
2 NIH, United States

* To whom correspondence should be addressed. E-mail: fjgonz{at}helix.nih.gov.

Objectives: Pregnane X receptor expression (PXR) has been shown to be protective in inflammatory bowel disease (IBD) in humans. However, the mechanism by which PXR provides protection remains unclear. Methods: Wild-type and Pxr-null mice were treated with the PXR agonist, pregnenolone-16{alpha}-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 assay and proinflammatory cytokine analysis were performed. Results: PXR agonist-treated mice were protected from DSS-induced colitis in comparison to vehicle-treated mice, as defined by body weight loss, diarrhea, rectal bleeding, colon length and histology. Pregnenolone-16{alpha}-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{kappa}B target genes in a PXR-dependent manner. Conclusions: The present study clearly demonstrates a protective role for PXR agonist in DSS-induced IBD. The data suggest that PXR-mediated repression of NF{kappa}B target genes in the colon is the mechanism by which PXR activation decreases susceptibility of mice to DSS-induced IBD.




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