Abstract
BackgroundThere is a need for novel anti-inflammatory therapies to treat COPD. The liver X receptor (LXR) is a nuclear hormone receptor with anti-inflammatory properties.MethodsWe investigated LXR gene and protein expression levels in alveolar macrophages and whole lung tissue from COPD patients and controls, the effect of LXR activation on the suppression of inflammatory mediators from LPS stimulated COPD alveolar macrophages, and the effect of LXR activation on the induction of genes associated with alternative macrophage polarisation.ResultsThe levels of LXR mRNA were significantly increased in whole lung tissue extracts in COPD patients and smokers compared to non-smokers. The expression of LXR protein was significantly increased in small airway epithelium and alveolar epithelium in COPD patients compared to controls. No differences in LXR mRNA and protein levels were observed in alveolar macrophages between patient groups. The LXR agonist GW3965 significantly induced the expression of the LXR dependent genes ABCA1 and ABCG1 in alveolar macrophage cultures. In LPS stimulated alveolar macrophages, GW3965 suppressed the production of CXCL10 and CCL5, whilst stimulating IL-10 production.ConclusionsGW3965 did not significantly suppress the production of TNFα, IL-1β, or CXCL8. Our major finding is that LXR activation has anti-inflammatory effects on CXC10, CCL5 and IL-10 production from alveolar macrophages.
Highlights
Cigarette smoking causes oxidative stress and inflammation in the airways [1], and is a major risk factor for the development of chronic obstructive pulmonary disease (COPD)
LXRα and LXRβ mRNA expression levels were significantly increased in COPD patients and S compared to NS (Figure 1)
Gene expression Having demonstrated that GW3965 inhibited LPS-induced CXCL10 protein secretion from alveolar macrophages, we investigated the effect of GW3965 on CXCL10 mRNA
Summary
Cigarette smoking causes oxidative stress and inflammation in the airways [1], and is a major risk factor for the development of chronic obstructive pulmonary disease (COPD). LXR gene expression was detectable in human alveolar macrophages, and GW3965 caused up to 60% inhibition of cytokine production from these cells. These findings suggest that LXR agonists may have the potential to reduce airway inflammation in COPD through the modulation of macrophage function. COPD alveolar macrophages are phenotypically different from healthy controls [19], and the effects of LXR activation on cytokine production may be altered It is not known whether LXR expression is changed within the lungs of COPD patients compared to controls. The liver X receptor (LXR) is a nuclear hormone receptor with anti-inflammatory properties
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