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J. Biol. Chem., Vol. 282, Issue 44, 31882-31890, November 2, 2007

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Novel Role for the Liver X Nuclear Receptor in the Suppression of Lung Inflammatory Responses^*

Mark A. Birrell, Matthew C. Catley, Elizabeth Hardaker, Sissie Wong, Timothy M. Willson, Kerryn McCluskie, Thomas Leonard^¶, Stuart N. Farrow^||, Jon L. Collins, Saleem Haj-Yahia^**, and Maria G. Belvisi¹

From the Respiratory Pharmacology Group, Airway Diseases Department, Faculty of Medicine, National Heart and Lung Institute, Imperial College, Dovehouse St., London SW3 6LY, United Kingdom, High Throughput Chemistry, Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, ^¶Center for Excellence in Drug Discovery, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, ^||Respiratory and Inflammation CEDD, GlaxoSmithKline, Stevenage SG1 2NY, United Kingdom, and ^**Royal Brompton and Harefield Hospital, London, United Kingdom

The liver X receptors (LXR/) are part of the nuclear receptor family and are believed to regulate cholesterol and lipid homeostasis. It has also been suggested that LXR agonists possess anti-inflammatory properties. The aim of this work was to determine the effect of LXR agonists on the innate immune response in human primary lung macrophages and a pre-clinical rodent model of lung inflammation. Before profiling the impact of the agonist, we established that both the human macrophages and the rodent lungs expressed LXR/. We then used two structurally distinct LXR agonists to demonstrate that activation of this transcription factor reduces cytokine production in THP-1 cells and lung macrophages. Then, using the expression profile of ATP binding cassettes A1 (ABCA-1; a gene directly linked to LXR activation) as a biomarker for lung exposure of the compound, we demonstrated an LXR-dependent reduction in lung neutrophilia rodents in vivo. This inhibition was not associated with a suppression of c-Fos/c-Jun mRNA expression or NF-B/AP-1 DNA binding, suggesting that any anti-inflammatory activity of LXR agonists is not via inhibition of NF-B/AP-1 transcriptional activity. These data do not completely rule out an impact of these agonists on these two prominent transcription factors. In summary, this study is the first to demonstrate anti-inflammatory actions of LXRs in the lung. Chronic innate inflammatory responses observed in some airway diseases is thought to be central to disease pathogenesis. Therefore, data suggest that LXR ligands have utility in the treatment of lung diseases that involves chronic inflammation mediated by macrophages and neutrophils.

Received for publication, April 18, 2007 , and in revised form, July 30, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 44-207-351-8270; Fax: 44-207-351-8173; E-mail: m.belvisi{at}imperial.ac.uk.

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