Liver X receptor stimulates cholesterol efflux and inhibits expression of proinflammatory mediators in human airway smooth muscle cells.
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; alpha and beta 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.
Delvecchio
Christopher J
CJ
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
Bilan
Patricia
P
Radford
Katherine
K
Stephen
Jancy
J
Trigatti
Bernardo L
BL
Cox
Gerard
G
Parameswaran
Krishnan
K
Capone
John P
JP
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000037:antagonists & inhibitors; D004268:DNA-Binding Proteins / Q000819:agonists / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D000071518:Liver X Receptors; D008168:Lung / Q000166:cytology / Q000276:immunology*; D032389:Myocytes, Smooth Muscle / Q000276:immunology*; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*
C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D016207:Cytokines; D004268:DNA-Binding Proteins; D018836:Inflammation Mediators; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D002784:Cholesterol