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,Maria G Belvisi

doi:10.1074/jbc.m703278200

Abstract

The liver X receptors (LXRalpha/beta) 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 LXRalpha/beta. 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-kappaB/AP-1 DNA binding, suggesting that any anti-inflammatory activity of LXR agonists is not via inhibition of NF-kappaB/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.

Highlights

liver X receptors (LXR)␣ and -␤ mRNA Expression in THP-1 Cells and Human Lung Tissue Macrophages (HLTMs)— The level of LXR mRNA expression appears to be comparable in THP-1 cells and HLTMs (Fig. 1)
Before profiling the impact of the LXR ligands in the primary lung macrophages, it was decided to determine whether the gene for the receptors was expressed in these primary cells, as they may be different from other non-lung-derived sources of macrophages
Treatment of LPS-stimulated THP-1 cells and primary human macrophages with either LXR ligand caused a concentrationrelated reduction in cytokine production

Summary

Introduction

The nuclear receptors LXR␣ and LXR␤ have been implicated in the control of cholesterol and fatty acid metabolism, and in the intestine ligand activation of LXR/RXR heterodimers dramatically reduces dietary cholesterol absorption, an effect postulated to be mediated by ABCA1 (6). A dual LXR␣/␤ agonist has been shown to reduce the development of atherosclerosis (9), and in a similar murine model the same authors found that two LXR␣/␤ agonists reduced inflammatory mRNA expression This data suggest that LXR agonists may reduce atherosclerosis by promoting cholesterol efflux and by limiting the production of inflammatory mediators in the artery wall (10). This anti-inflammatory profile has been shown in two murine models of contact dermatitis (11). In parallel, having shown that the airways of the rat strain used in the pre-clinical model expressed LXR, we used the expression of ABCA-1 as a guide for determining the dose of compound to be used to profile their effect in vivo

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