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The PXR is a drug target for chronic inflammatory liver disease

Lookup NU author(s): Dr Karen Wallace, Dr David Cowie, Stephen Hill, Andy Axon, Steven White, Professor Derek Mann, Professor Matthew Wright

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Abstract

PXR activators are used to treat pruritus in chronic inflammatory liver diseases such as primary biliary cirrhosis (PBC). The aims of this study were to determine whether PXR activators could have an additional benefit of inhibiting inflammation in the liver, and determine whether cyclosporin A - which more effectively prevents PBC recurrence in transplanted patients than FK506 - is a PXR activator. In SJL/J mice (which have constitutively high levels of hepatic portal tract inflammatory cell recruitment), feeding a PXR activator inhibited inflammation, TNF alpha and II-1 alpha mRNA expression in SJL/J-PXR+/+, but not SJL/J-PXR-/-. Monocytic cells - a major source of inflammatory mediators such as TNF alpha - expressed the PXR and PXR activators inhibited endotoxin-induced NF-kappa B activation and TNF alpha expression. PXR activation also inhibited endotoxin-stimulated TNF alpha secretion from liver monocytes/macrophages isolated from PXR+/+ mice, but not from cells isolated from PXR-/- mice. To confirm that PXR activation inhibits NF-kappa B in vivo, 3x-kappa B-luc fibrotic mice (which express a luciferase gene regulated by NF-kappa B) were imaged after treatment with the hepatotoxin CCl4. PXR activator inhibited the induction of hepatic NF-kappa B activity without affecting CCl4 toxicity/hepatic damage. Using a PXR reporter gene assay, cyclosporin A - but not FK506 - was shown to be a direct PXR activator, and also to induce expression of the classic PXR-regulated CYP3A4 gene in human hepatocytes and in a cell line null for the FXR, a nuclear receptor with similar properties to the PXR. Conclusion: PXR activation is anti-inflammatory in the liver and the effects of cyclosporin A in PBC disease recurrence may be mediated in part via the PXR. Since PXR activation promotes hepatocyte growth and is also anti-fibrogenic. the PXR may be an excellent drug target for the treatment of chronic inflammatory liver disease. (C) 2010 Elsevier Ltd. All rights reserved.


Publication metadata

Author(s): Wallace K, Cowie DE, Konstantinou DK, Hill SJ, Tjelle TE, Axon A, Koruth M, White SA, Carlsen H, Mann DA, Wright MC

Publication type: Article

Publication status: Published

Journal: Journal of Steroid Biochemistry and Molecular Biology

Year: 2010

Volume: 120

Issue: 2-3

Pages: 137-148

Print publication date: 21/04/2010

ISSN (print): 0960-0760

ISSN (electronic): 1879-1220

Publisher: Pergamon

URL: http://dx.doi.org/10.1016/j.jsbmb.2010.04.012

DOI: 10.1016/j.jsbmb.2010.04.012


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