Thioredoxin-1 and its natural inhibitor, vitamin D3 up-regulated protein 1, are differentially regulated by PPARalpha in human macrophages.
Macrophage-derived reactive oxygen species contribute to the initiation and development of atherosclerosis. The cellular balance between oxidative and reductive states depends on the endogenous antioxidant capacity, with the thioredoxin-1 (Trx-1) system playing a major role. Peroxisome proliferator-activated receptor-alpha (PPARalpha) is expressed by human macrophages and exhibits anti-inflammatory properties. Here we show that the selective PPARalpha activator GW647 significantly increased the Trx-1 mRNA and protein expression in human macrophages as determined by quantitative polymerase chain reaction and Western immunoblotting. Consistently, the Trx-1 activity was significantly increased by PPARalpha activation. By contrast, PPARalpha activation led to the down-regulation of vitamin D(3) up-regulated protein 1 (VDUP-1), the physiological inhibitor of Trx-1. Analysis of the Trx-1 and VDUP-1 promoters with gene reporter assays, mutational analysis, gel shift assays and chromatin immunoprecipitation analyses revealed the presence of a functional response element specific for PPARalpha in the Trx-1 promoter and the presence of a functional activator protein 1 (AP-1) site in the VDUP-1 promoter. The interference of PPARalpha/retinoid X receptor alpha with the AP-1 transcription factor elements c-Jun/c-Fos resulted in the inhibition of AP-1 binding and down-regulation of the VDUP-1 gene expression. Finally, PPARalpha activation reduced the lidocaine-induced caspase-3 activity and apoptosis, which might be due to the VDUP-1-mediated regulation of the Bax/Bcl-2 ratio. Together these data indicate that stimulation of PPARalpha in human macrophages might reduce arterial inflammation through differential regulation of the Trx-1 and VDUP-1 gene expression.
UMR-7079, Université Pierre et Marie Curie/CNRS, Bâtiment A, 5ème étage/Case courrier 256, 7, Quai St-Bernard, 75252 Paris Cedex 5, France.
Ludivine
L
Billiet
Christophe
C
Furman
Clarisse
C
Cuaz-Pérolin
Réjane
R
Paumelle
Michel
M
Raymondjean
Thomas
T
Simmet
Mustapha
M
Rouis
D017209:Apoptosis; D001483:Base Sequence; D001665:Binding Sites; D002087:Butyrates / Q000494:pharmacology; D002352:Carrier Proteins / Q000096:biosynthesis*; D002843:Chromatin / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D008969:Molecular Sequence Data; D018384:Oxidative Stress; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D013879:Thioredoxins / Q000096:biosynthesis*; D018808:Transcription Factor AP-1 / Q000378:metabolism
D002087:Butyrates; D002352:Carrier Proteins; D002843:Chromatin; C453899:GW 7647; D047493:PPAR alpha; D010671:Phenylurea Compounds; C486715:TXNIP protein, human; D018808:Transcription Factor AP-1; D013879:Thioredoxins