Pregnane X receptor activation ameliorates DSS-induced inflammatory bowel disease via inhibition of NF-kappaB target gene expression.
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.
Shah
Yatrik M
YM
Laboratory of Metabolism, Center of Cancer Research, National Cancer Institute, National Institutes of health, Bldg. 37, Rm. 3106, Bethesda, MD 20892, USA.
Ma
Xiaochao
X
Morimura
Keiichirou
K
Kim
Insook
I
Gonzalez
Frank J
FJ
D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D005765:Gastrointestinal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015870:Gene Expression / Q000187:drug effects; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D000077297:Pregnane X Receptor; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D011987:Receptors, Steroid / Q000819:agonists* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000819:agonists / Q000378:metabolism; D012720:Severity of Illness Index; D013997:Time Factors; D014162:Transfection
D018528:ATP-Binding Cassette Transporters; D016207:Cytokines; D005765:Gastrointestinal Agents; D016328:NF-kappa B; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid; D012097:Repressor Proteins; D011285:Pregnenolone Carbonitrile; D016264:Dextran Sulfate; D005982:Glutathione Transferase