Received for publication August 4, 2006.
Revised November 27, 2006.
Accepted for publication December 1, 2006.

DIFFERENTIAL REGULATION OF HEPATIC TRANSPORTERS IN THE ABSENCE OF TNF-, IL-1, IL-6 AND NF-B IN TWO MODELS OF CHOLESTASIS

Abstract

Hepatic transporters are responsible for uptake and efflux of bile acids and xenobiotics as an essential aspect of liver function. When normal vectorial transport of bile acids by the apical uptake and canalicular excretion transporters is disrupted, cholestasis ensues, leading to accumulation of toxic bile constituents and considerable hepatocellular damage. The purpose of this study was to assess the role of cytokines and Nuclear Factor-B (NF-B) in the transcriptional regulation of transporters in two models of cholestasis, lipopolysaccharide (LPS) administration and bile-duct ligation (BDL). In wild type (WT) and knockout mouse strains lacking TNF Receptor-1 (TNFR1), Interleukin (IL)-1-Receptor I (RI), IL-6 or IB kinase , transporter mRNA levels in liver were determined using branched DNA signal amplification 16h following LPS administration or 3 days after BDL. In WT mice, LPS administration tended to decrease mRNA levels of Oat2, Ntcp, Oatp1, Oatp4, Bsep, Mrp2 and Mrp6 compared to saline treatment, whereas it increased Mrp1, 3 and 5 levels. Similar changes were observed in each knockout strain following LPS administration. Conversely, BDL decreased only Oatp1 expression in WT mice, meanwhile increasing expression of Mrp1, 3, 5, and Oatp2 expression in both WT and knockout strains. Because the transcriptional effects of BDL- and LPS-induced cholestasis reflect dissimilarity in hepatic transporter regulation, we conclude that these disparities are not due to the individual activity of TNF-, IL-1, IL-6 or NF-B, but to the differences in the mechanism of cholestasis.

Key words: cytokines, gene regulation, hepatobiliary transport, liver disease, MRP, organic anion transport, transcriptional regulation, transporters

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