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dc.contributor.authorZhou, Changchengen_US
dc.contributor.authorTabb, Michelle M.en_US
dc.contributor.authorNelson, Edward L.en_US
dc.contributor.authorGrün, Felixen_US
dc.contributor.authorVerma, Sumanen_US
dc.contributor.authorSadatrafiei, Asalen_US
dc.contributor.authorLin, Minen_US
dc.contributor.authorMallick, Shyamalien_US
dc.contributor.authorForman, Barry M.en_US
dc.contributor.authorThummel, Kenneth E.en_US
dc.contributor.authorBlumberg, Bruceen_US
dc.date.accessioned2010-05-06T20:07:36Z
dc.date.available2010-05-06T20:07:36Z
dc.date.issued2006-07-01en_US
dc.identifier.citationZhou C, Tabb MM, Nelson EL, et al. Mutual repression between steroid and xenobiotic receptor and NF-κB signaling pathways links xenobiotic metabolism and inflammation. J Clin Invest. 2006;116(8):2280-2289.en_US
dc.identifier.other10.1172/JCI26283en_US
dc.identifier.urihttp://www.jci.org/articles/view/26283en_US
dc.identifier.urihttp://hdl.handle.net/1773/15858
dc.description.abstractWhile it has long been known that inflammation and infection reduce expression of hepatic cytochrome P450 (CYP) genes involved in xenobiotic metabolism and that exposure to xenobiotic chemicals can impair immune function, the molecular mechanisms underlying both of these phenomena have remained largely unknown. Here we show that activation of the nuclear steroid and xenobiotic receptor (SXR) by commonly used drugs in humans inhibits the activity of NF-κB, a key regulator of inflammation and the immune response. NF-κB target genes are upregulated and small bowel inflammation is significantly increased in mice lacking the SXR ortholog pregnane X receptor (PXR), thereby demonstrating a direct link between SXR and drug-mediated antagonism of NF-κB. Interestingly, NF-κB activation reciprocally inhibits SXR and its target genes whereas inhibition of NF-κB enhances SXR activity. This SXR/PXR–NF-κB axis provides a molecular explanation for the suppression of hepatic CYP mRNAs by inflammatory stimuli as well as the immunosuppressant effects of xenobiotics and SXR-responsive drugs. This mechanistic relationship has clinical consequences for individuals undergoing therapeutic exposure to the wide variety of drugs that are also SXR agonists.en_US
dc.description.sponsorshipGrants from the NIH (GM-60572), US Environmental Protection Agency (STAR R830686), and the Department of Defense (DAMD17-02-1-0323) to B. Blumberg, and the NIH (AT00886) to B.M. Forman and (GM063666) to K.E. Thummel.en_US
dc.language.isoen_USen_US
dc.titleMutual repression between steroid and xenobiotic receptor and NF-κB signaling pathways links xenobiotic metabolism and inflammationen_US


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