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Liver X Receptor Stimulates Cholesterol Efflux and Inhibits Expression of Proinflammatory Mediators in Human Airway Smooth Muscle Cells

Department of Biochemistry and Biomedical Sciences (C.J.D., P.B., B.L.T., J.P.C.) and Department of Medicine (G.C., K.P.), McMaster University, Hamilton, Ontario, Canada L83 4K1; and Firestone Institute for Respiratory Health (K.R., J.S., G.C., K.P.), St. Joseph’s Healthcare, Hamilton, Ontario, Canada L8N 4A6

Address all correspondence and requests for reprints to: John P. Capone, Faculty of Science, 1280 Main Street West, GSB Room 114/B, McMaster University, Hamilton, Ontario, Canada L83 4K1. E-mail: caponej{at}mcmaster.ca.

Human (h) airway smooth muscle (ASM) cells are important mediators of the inflammatory process observed in asthma and other respiratory diseases. We show here that primary hASM cells express liver X receptor (LXR; and ß subtypes), an oxysterol-activated nuclear receptor that controls expression of genes involved in lipid and cholesterol homeostasis, and inflammation. LXR was functional as determined by transient assays using LXR-responsive reporter genes and by analysis of mRNA and protein expression of endogenous LXR target genes in cells exposed to LXR agonists. LXR activation induced expression of the ATP-binding cassette transporters ABCA1 and ABCG1 and increased efflux of cholesterol to apolipoprotein AI and high-density lipoprotein acceptors, pointing to a role for hASM cells in modulating cholesterol homeostasis in the airway. Under inflammatory conditions, hASM cells release a variety of chemokines and cytokines that contribute to inflammatory airway diseases. Activation of LXR inhibited the expression of multiple cytokines in response to proinflammatory mediators and blocked the release of both granulocyte macrophage colony-stimulating factor and granulocyte colony stimulating factor. LXR activation also inhibited proliferation of hASM cells and migration toward platelet-derived growth factor chemoattractant, two important processes that contribute to airway remodeling. Our findings reveal biological roles for LXR in ASM cells and suggest that modulation of LXR activity offers prospects for new therapeutic approaches in the treatment of asthma and other inflammatory respiratory diseases.

NURSA Molecule Pages Link:

Nuclear Receptors:   LXRβ  |  LXRα  |  FXRα  |  PXR

Ligands:   T0901317  |  GW 3965  |  Dexamethasone  |  9-cis-Retinoic acid

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