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Research ArticleArticle

Pregnane X Receptor Modulates the Inflammatory Response in Primary Cultures of Hepatocytes

Mengxi Sun, Wenqi Cui, Sarah K. Woody and Jeff L. Staudinger
Drug Metabolism and Disposition March 2015, 43 (3) 335-343; DOI: https://doi.org/10.1124/dmd.114.062307
Mengxi Sun
Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, Kansas
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Wenqi Cui
Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, Kansas
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Sarah K. Woody
Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, Kansas
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Jeff L. Staudinger
Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, Kansas
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Abstract

Bacterial sepsis is characterized by a rapid increase in the expression of inflammatory mediators to initiate the acute phase response in liver. Inflammatory mediator release is counterbalanced by the coordinated expression of anti-inflammatory molecules such as interleukin 1 receptor antagonist (IL1-Ra) through time. This study determined whether activation of pregnane X receptor (PXR, NR1I2) alters the lipopolysaccharide (LPS)-inducible gene expression program in primary cultures of hepatocytes (PCHs). Preactivation of PXR for 24 hours in PCHs isolated from wild-type mice suppressed the subsequent LPS-inducible expression of the key inflammatory mediators interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor α (TNFα) but not in PCHs isolated from Pxr-null (PXR-knockout [KO]) mice. Basal expression of key inflammatory cytokines was elevated in PCHs from PXR-KO mice. Stimulation of PCHs from PXR-KO mice with LPS alone produced enhanced levels of IL-1β when compared with wild-type mice. Experiments performed using PCHs from both humanized-PXR transgenic mice as well as human donors indicate that prolonged activation of PXR produces an increased secretion of IL1-Ra from cells through time. Our data reveal a working model that describes a pivotal role for PXR in both inhibiting as well as in resolving the inflammatory response in hepatocytes. Understanding the molecular details of how PXR is converted from a positive regulator of drug-metabolizing enzymes into a transcriptional suppressor of inflammation in liver will provide new pharmacologic strategies for modulating inflammatory-related diseases in the liver and intestine.

Footnotes

    • Received July 21, 2014.
    • Accepted December 12, 2014.
  • This work was supported by the National Institutes of Health National Institute Diabetes and Digestive and Kidney Diseases (NIDDK) [Grant R01 DK090558]. The human hepatocytes used in this study were derived from samples collected and provided by the University of Kansas Medical Center (KUMC) Department of Pharmacology, Toxicology and Therapeutics Hepatocyte Core Laboratory and the KU Liver Center.

  • dx.doi.org/10.1124/dmd.114.062307.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (3)
Drug Metabolism and Disposition
Vol. 43, Issue 3
1 Mar 2015
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Research ArticleArticle

Pregnane X Receptor Inhibits the Acute Phase Response

Mengxi Sun, Wenqi Cui, Sarah K. Woody and Jeff L. Staudinger
Drug Metabolism and Disposition March 1, 2015, 43 (3) 335-343; DOI: https://doi.org/10.1124/dmd.114.062307

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Research ArticleArticle

Pregnane X Receptor Inhibits the Acute Phase Response

Mengxi Sun, Wenqi Cui, Sarah K. Woody and Jeff L. Staudinger
Drug Metabolism and Disposition March 1, 2015, 43 (3) 335-343; DOI: https://doi.org/10.1124/dmd.114.062307
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