Published online before print March 24, 2005, doi: 10.1161/01.RES.0000163630.86796.17
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© 2005 American Heart Association, Inc.
UltraRapid Communication |
Liver X Receptor Agonists Inhibit Cytokine-Induced Osteopontin Expression in Macrophages Through Interference With Activator Protein-1 Signaling Pathways
From the Division of Endocrinology and Molecular Medicine (D.O., J.F.S., D.B.), University of Kentucky College of Medicine, Lexington, Ken; Division of Endocrinology (Y.T., F.B., V.H.C., R.E.L., W.A.H.), Diabetes and Hypertension, David Geffen School of Medicine, University of California, Los Angeles, Calif; and the Division of Bone and Mineral Diseases (D.W.T.), Washington University Medical Center, St Louis, Mo.
Correspondence to Dennis Bruemmer, MD, University of Kentucky College of Medicine, Department of Internal Medicine, Division of Endocrinology and Molecular Medicine, Wethington Health Sciences Bldg, Rm 575, 900 South Limestone St, Lexington, KY 40536-0200. E-mail Dennis.Bruemmer{at}uky.edu
Osteopontin (OPN) is a proinflammatory cytokine and adhesion molecule implicated in the chemoattraction of monocytes and in cell-mediated immunity. We have recently reported that genetic OPN-deficiency attenuates the development of atherosclerosis in apoE–/– mice identifying OPN as potential target for pharmacological intervention in atherosclerosis. Synthetic agonists for the Liver X Receptor (LXR), members of the nuclear hormone receptor superfamily, prevent the development of atherosclerosis by regulating cholesterol homeostasis and suppressing inflammatory gene expression in macrophages. We demonstrate here that LXR ligands inhibit cytokine-induced OPN expression in macrophages. Two synthetic LXR ligands, T0901317 and GW3965, inhibited TNF-
, IL-1ß, INF-
and lipopolysaccharide induced OPN mRNA and protein expression in RAW 264.7 macrophages. Transient transfection experiments revealed that LXR ligands suppress cytokine-induced OPN promoter activity. Deletion analysis, heterologous promoter assays, and site-directed mutagenesis identified an activator protein-1 (AP-1) consensus site at -76 relative to the initiation site that supports OPN transcription in macrophages and mediates the effects of LXR ligands to inhibit OPN transcription. Electrophoretic mobility shift and chromatin immunoprecipitation assays indicated that LXR agonists inhibit cytokine-induced c-Fos and phospho-c-Jun binding to this AP-1 site. Cytokine-induced c-Fos and phospho-c-Jun protein expression was inhibited by LXR ligands and overexpression of c-Fos and c-Jun reversed the inhibitory effect of LXR ligands on OPN promoter activity in transactivation assays. Finally, treatment of C57BL/6J mice with LXR ligands inhibited OPN expression in peritoneal macrophages indicating that the observed effects of LXR ligands to inhibit OPN expression are applicable in vivo. These observations identify the regulation of macrophage OPN expression as a mechanism whereby LXR ligands may impact macrophage inflammatory responses and atherosclerosis. The full text of this article is available online at http://circres.ahajournals.org.
Key Words: osteopontin • liver X receptor • nuclear receptor • activator protein-1
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