Document Detail


Liver x receptor agonists inhibit cytokine-induced osteopontin expression in macrophages through interference with activator protein-1 signaling pathways.
MedLine Citation:
PMID:  15790955     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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-alpha, IL-1beta, INF-gamma 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.
Authors:
Daisuke Ogawa; Jeffrey F Stone; Yasunori Takata; Florian Blaschke; Van H Chu; Dwight A Towler; Ronald E Law; Willa A Hsueh; Dennis Bruemmer
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2005-03-24
Journal Detail:
Title:  Circulation research     Volume:  96     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2005 Apr 
Date Detail:
Created Date:  2005-04-15     Completed Date:  2005-10-11     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e59-67     Citation Subset:  IM    
Affiliation:
Division of Endocrinology and Molecular Medicine, University of Kentucky College of Medicine, Lexington, Ken 40536-0200, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cells, Cultured
Cytokines / pharmacology*
DNA-Binding Proteins / agonists,  physiology*
Macrophages / metabolism*
Mice
Mice, Inbred C57BL
Octamer Transcription Factor-1
Orphan Nuclear Receptors
Osteopontin
Promoter Regions, Genetic
Proto-Oncogene Proteins c-fos / analysis
RNA, Messenger / analysis
Receptors, Cytoplasmic and Nuclear / agonists,  physiology*
Sialoglycoproteins / genetics*
Signal Transduction / physiology*
Transcription Factor AP-1 / metabolism*
Transcription Factors / physiology
Upstream Stimulatory Factors
Grant Support
ID/Acronym/Agency:
HL 58328/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Cytokines; 0/DNA-Binding Proteins; 0/Octamer Transcription Factor-1; 0/Orphan Nuclear Receptors; 0/Pou2f1 protein, mouse; 0/Proto-Oncogene Proteins c-fos; 0/RNA, Messenger; 0/Receptors, Cytoplasmic and Nuclear; 0/Sialoglycoproteins; 0/Spp1 protein, mouse; 0/Transcription Factor AP-1; 0/Transcription Factors; 0/Upstream Stimulatory Factors; 0/liver X receptor; 106441-73-0/Osteopontin

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