Thioredoxin-1 and Its Natural Inhibitor, Vitamin D3 Up-Regulated Protein 1, Are Differentially Regulated by PPARα in Human Macrophages

Abstract

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-α (PPARα) is expressed by human macrophages and exhibits anti-inflammatory properties. Here we show that the selective PPARα 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 PPARα activation. By contrast, PPARα activation led to the down-regulation of vitamin D3 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 PPARα 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 PPARα/retinoid X receptor α 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, PPARα 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 PPARα in human macrophages might reduce arterial inflammation through differential regulation of the Trx-1 and VDUP-1 gene expression.