Mutual repression between steroid and xenobiotic receptor and NF-κB signaling pathways links xenobiotic metabolism and inflammation

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Mutual repression between steroid and xenobiotic receptor and NF-κB signaling pathways links xenobiotic metabolism and inflammation

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dc.contributor.author Zhou, Changcheng en_US
dc.contributor.author Tabb, Michelle M. en_US
dc.contributor.author Nelson, Edward L. en_US
dc.contributor.author Grün, Felix en_US
dc.contributor.author Verma, Suman en_US
dc.contributor.author Sadatrafiei, Asal en_US
dc.contributor.author Lin, Min en_US
dc.contributor.author Mallick, Shyamali en_US
dc.contributor.author Forman, Barry M. en_US
dc.contributor.author Thummel, Kenneth E. en_US
dc.contributor.author Blumberg, Bruce en_US
dc.date.accessioned 2010-05-06T20:07:36Z
dc.date.available 2010-05-06T20:07:36Z
dc.date.issued 2006-07-01 en_US
dc.identifier.citation Zhou 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.other 10.1172/JCI26283 en_US
dc.identifier.uri http://www.jci.org/articles/view/26283 en_US
dc.identifier.uri http://hdl.handle.net/1773/15858
dc.description.abstract While 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.sponsorship Grants 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.iso en_US en_US
dc.title Mutual repression between steroid and xenobiotic receptor and NF-κB signaling pathways links xenobiotic metabolism and inflammation en_US


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