Novel Role For The liver X Nuclear Receptor In The Suppression Of lung Inflammatory Responses.

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Journal Title, Volume, Page: 
THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 282, NO. 44, pp. 31882–31890, November 2, 2007
Year of Publication: 
Mark A. Birrell
Matthew C. Catley
Elizabeth Hardaker
Sissie Wong
Timothy M. Willson
Kerryn McCluskie
Thomas Leonard
Thomas Leonard
Jon L. Collins
Saleem Haj-Yahia
Maria G. Belvisi
Preferred Abstract (Original): 

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

The liver X receptors (LXR)2 are part of the nuclear receptor super family and exist in two forms known as LXRα and LXRβ. These receptors are coded by two separate genes, Nr1h3 and Nr1h2, respectively (1). LXRs form obligate heterodimers with another orphan nuclear receptor, RXR, and regulate cholesterol and lipid homeostasis. Originally it was believed that LXRs were orphan receptors until the discovery of endogenous ligands; that is, the oxysterols (14). LXR directly controls the transcription of several genes involved in the cholesterol efflux pathway including ATP binding cassettes A1 (ABCA-1) and G1 (58). The nuclear receptors LXRα and LXRβ 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 LXRα/β agonist has been shown to reduce the development of atherosclerosis (9), and in a similar murine model the same authors found that two LXRα/β agonists reduced inflammatory mRNA expression. This data suggest that LXR agonists may reduce atherosclerosis not only by promoting cholesterol efflux but also by limiting the production of inflammatory mediators in the artery wall (10). This anti-inflammatory profile has also been shown in two murine models of contact dermatitis (11).

In cultured mouse macrophages, human blood-derived macrophages, and a macrophage cell line, LXRα/β agonists have been shown to reduce inflammatory mediator production (e.g. nitric oxide (10, 12), inflammatory cytokines (10, 1316), and matrix metalloproteinase 9 (17). Therefore, there is a clear rationale for evaluating the ability of LXR ligands to evoke anti-inflammatory activity in the lung (1820).

The aim of this study was to determine the effect of two structurally distinct LXR agonists, GW3965 and T1317, on the response to LPS in the airways. The innate inflammatory response to endotoxin is central to host defense processes, but in disease conditions, this chronic inflammatory response can become detrimental to the airways. As yet there are no published studies on the impact of LXR agonists in the airways; therefore, the first challenge was to determine whether LXR receptors are expressed in the in vitro and in vivo systems we were to use. Having demonstrated the presence of the receptors in both cell types, we profiled the impact of the two LXR agonists in the LPS-driven cytokine release in the human cell-based assays. 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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