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INFLAMMATION/IMMUNITY/MEDIATORS
1Department of Internal Medicine III, Aachen University, University Hospital, Aachen, Germany; 2Department of Pediatrics, Mount Sinai Medical Center, New York, New York; 3Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University Graz, Graz, Austria; and 4Institute of Biomedical Technologies, University of Pisa, Consiglio Nazionale delle Ricerche, Pisa, Italy
Submitted 13 July 2004 ; accepted in final form 26 April 2005
Proinflammatory cytokines such as TNF-
and IL-1
lead to downregulation of hepatic organic anion transporters in cholestasis. This adapted response is transcriptionally mediated by nuclear hormone receptors and liver-specific transcription factors. Because little is known in vivo about cytokine-dependent regulatory events, mice were treated with either TNF- or IL-1 for up to 16 h. Transporter mRNA expression was determined by Northern blot analysis, nuclear activity, and protein-expression of transactivators by EMSA and Western blotting. TNF- induces a sustained decrease in Ntcp, Oatp1/Oatp1a1, and Bsep mRNA expression but exerts only transient [multidrug resistance-associated protein 2 (Mrp2)] or no effects (Mrp3) on Mrps. In addition to Ntcp and Oatp1/Oatp1a1, IL-1 also downregulates Bsep, Mrp2, and Mrp3 mRNAs to some extent. To study transcriptional regulation, Ntcp and Bsep promoters were first cloned from mice revealing a new distal Ntcp hepatocyte nuclear factor 1 (HNF-1) element but otherwise show a conserved localization to known rat regulatory elements. Changes in transporter-expression are preceeded by a reduction in binding activities at IR-1, ER-8, DR-5, and HNF-1 sites after 4 h by either cytokine, which remained more sustained by TNF- in the case of nuclear receptors. Nuclear protein levels of retinoid X receptor (RXR)- are significantly decreased by TNF- but only transiently affected by IL-1. Minor reductions of retinoic acid receptor, farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor nuclear proteins are restricted to 4 h after cytokine application and paralleled by a decrease in mRNA levels. Basolateral and canalicular transporter systems are downregulated by both cytokines, TNF- and IL-1. Activity of HNF-1 as regulator of mNtcp is suppressed by both cytokines. Decreased binding activities of nuclear receptor heterodimers may be explained by a reduction of the ubiquitous heterodimerization partner RXR-.
cholestasis; tumor necrosis factor-; interleukin-1; nuclear hormone receptors; gene expression
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