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Am J Physiol Gastrointest Liver Physiol (April 28, 2005). doi:10.1152/ajpgi.00307.2004
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Submitted on July 13, 2004
Accepted on April 26, 2005

Cytokine-dependent regulation of hepatic organic anion transporter gene transactivators in mouse liver

Andreas Geier1*, Christoph G. Dietrich1, Sebastian Voigt1, Meenakshisundaram Ananthanarayanan2, Frank Lammert1, Anne Schmitz1, Michael Trauner3, Hermann E. Wasmuth1, Diana Boraschi4, Natarajan Balasubramaniyan2, Frederick J. Suchy2, Siegfried Matern1, and Carsten Gartung1

1 Department of Internal Medicine III, Aachen University (RWTH), Aachen, Germany
2 Department of Pediatrics, Mount Sinai Medical School, New York, NY, USA
3 Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria
4 Institute of Biomedical Technologies, University of Pisa, Pisa, Italy

* To whom correspondence should be addressed. E-mail: ageier{at}ukaachen.de.

Background: Proinflammatory cytokines such as TNF{alpha} and IL-1{beta} lead to down-regulation of hepatic organic anion transporters in cholestasis. This adapted response is transcriptionally mediated by nuclear hormone receptors and liver-specific transcription factors. Aim: Since little is known in vivo about cytokine-dependent regulatory events, mice were treated with either TNF{alpha} or IL-1{beta} up to 16h. Methods: Transporter mRNA-expression was determined by Northern analysis, nuclear activity and protein-expression of transactivators by EMSA and Western blotting. Results: TNF{alpha} induces a sustained decrease in Ntcp, Oatp1/Oatp1a1 and Bsep mRNA-expression, but exerts only transient (Mrp2) or no effects (Mrp3) on Mrps. In addition to Ntcp and Oatp1/Oatp1a1 IL-1{beta} also down-regulates 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 NtcpHNF1-element, but otherwise show a conserved localization to known rat regulatory elements. Changes in transporter-expression are preceeded by reduction in binding-activities at IR-1, ER-8, DR-5 and HNF1{alpha} sites after 4h by either cytokine, which remained more sustained by TNF{alpha} in case of nuclear receptors. Nuclear protein levels of RXR{alpha} are significantly decreased by TNF{alpha}, but only transiently affected by IL-1{beta}. Minor reductions of RAR, FXR, PXR and CAR nuclear proteins are restricted to 4h after cytokine-application and paralleled by a decrease in mRNA levels. Conclusions: Basolateral and canalicular transporter-systems are down-regulated by both cytokines, TNF{alpha} and IL-1{beta}. Activity of HNF1{alpha} 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{alpha}.




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