{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T13:56:19Z","timestamp":1791122179035,"version":"4.1.0"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":4414,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2003,8]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>Hepatobiliary transporters are down\u2013regulated in toxic and cholestatic liver injury. Cytokines such as tumor necrosis factor \u03b1 (TNF\u2013\u03b1) and interleukin 1\u03b2 (IL\u20131\u03b2) are attributed to mediate this regulation, but their particular contribution <jats:italic toggle=\"yes\">in vivo<\/jats:italic> is still unknown. Thus, we studied the molecular mechanisms by which Ntcp, Oatp1, Oatp2, and Mrp2 are regulated by proinflammatory cytokines during liver injury. Rats were injected intraperitoneally with either carbon tetrachloride or endotoxin. Inactivation of TNF\u2013\u03b1 and IL\u20131\u03b2 was achieved by repetitive intraperitoneal injection of etanercept and anakinra, respectively. Messenger RNA (mRNA) levels of transporters and binding activities as well as nuclear protein levels of <jats:italic toggle=\"yes\">Ntcp<\/jats:italic>, <jats:italic toggle=\"yes\">Oatp2<\/jats:italic>, and <jats:italic toggle=\"yes\">Mrp2<\/jats:italic> transactivators were determined 20 to 24 hours later. In contrast to IL\u20131\u03b2, TNF\u2013\u03b1 inactivation alone fully prevented down\u2013regulation of Ntcp, Oatp1, and Oatp2 mRNA as well as reduced binding activity of hepatocyte nuclear factor 1 (HNF\u20131) in CCl<jats:sub>4<\/jats:sub>\u2013induced toxic injury. In endotoxemia, down\u2013regulation of Mrp2, and partially in case of Ntcp, could be prevented by IL\u20131\u03b2 but not TNF\u2013\u03b1 blockade. However, inactivation of either cytokine led to preservation of HNF1 and partially of retinoid X receptor\/retinoic acid receptor (RXR\/RAR) binding activity. No effect of anticytokines was seen on pregnane X receptor (PXR) and constitutive androstane receptor (CAR) binding activity as well as nuclear protein mass. In conclusion, TNF\u2013\u03b1 represents the master cytokine responsible for HNF1\u2013dependent down\u2013regulation of <jats:italic toggle=\"yes\">Ntcp<\/jats:italic>, <jats:italic toggle=\"yes\">Oatp1<\/jats:italic>, and <jats:italic toggle=\"yes\">Oatp2<\/jats:italic> in CCl<jats:sub>4<\/jats:sub>\u2013induced toxic liver injury. IL\u20131\u03b2 predominates in a complex signaling network of <jats:italic toggle=\"yes\">Ntcp<\/jats:italic> and <jats:italic toggle=\"yes\">Mrp2<\/jats:italic> regulation in cholestatic liver injury. In contrast to <jats:italic toggle=\"yes\">in vitro<\/jats:italic> studies, HNF1 and RXR\/RAR\u2013independent mechanisms appear to be more important in regulation of <jats:italic toggle=\"yes\">Mrp2<\/jats:italic> and <jats:italic toggle=\"yes\">Ntcp<\/jats:italic> gene expression in endotoxemia.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1053\/jhep.2003.50317","type":"journal-article","created":{"date-parts":[[2003,7,25]],"date-time":"2003-07-25T19:11:16Z","timestamp":1059160276000},"page":"345-354","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":191,"title":["Effects of Proinflammatory Cytokines on Rat Organic Anion Transporters During Toxic Liver Injury and Cholestasis"],"prefix":"10.1097","volume":"38","author":[{"given":"Andreas","family":"Geier","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph 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In vitro transcription with nuclear extracts from differentiated tissues. In: , eds. Gene Transcription. 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