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INFLAMMATION AND IMMUNOPHARMACOLOGY
Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada
Inflammation and proinflammatory cytokines suppress the expression of several hepatic transporters and metabolic enzymes, often resulting in cholestatic liver disease. However, mechanism(s) of this down-regulation have not been fully elucidated. As the pregnane X receptor (PXR) is involved in inducing many of these hepatic proteins, it is possible that PXR is also involved in their down-regulation during inflammation. Thus, we compared the effect of inflammation on hepatic gene regulation in wild-type (PXR+/+) versus PXR-null (PXR-/-) mice. Treatment of PXR+/+ but not PXR-/- mice with the PXR activators 5-pregnen-3
-ol-20-one-16
-carbonitrile (PCN) or 17-hydroxy-11-[4-dimethylamino phenyl]-17-[1-propynyl] estra-4,9-dien-3-one (RU486) resulted in increased mRNA levels of bsep, mdr1a, mrp2, mrp3, oatp2, and cyp3a11, indicating involvement of PXR in their regulation. Significantly lower mRNA levels of bsep, mdr2, mrp2, mrp3, ntcp, oatp2, and cyp3a11 were found in endotoxin-treated PXR+/+ mice. In endotoxin-treated PXR-/- mice, the extent of mrp2 suppression was significantly diminished. Changes in MRP2 expression were supported by Western blot analysis. Although interleukin (IL)-6 imposed significant decreases in the expression of bsep, mrp2, and cyp3a11 in PXR+/+ mice, this was not observed in PXR-/- mice. Of note, significantly lower levels of PXR mRNA and protein were detected in endotoxin- and IL-6-treated PXR+/+ mice. In addition, endotoxin and IL-6 were also able to suppress PCN-mediated induction of bsep, mrp2, cyp3a11, and PXR. Taken together, our results suggest that PXR plays a role in the down-regulation of several hepatic proteins during inflammation.
Address correspondence to: Dr. Micheline Piquette-Miller, Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 19 Russell Street, Toronto, Ontario, Canada, M5S 2S2. E-mail: m.piquette.miller{at}utoronto.ca
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