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Enhanced VDUP‐1 gene expression by PPARγ agonist induces apoptosis in human macrophage

The fate and phenotype of lesion macrophages is regulated by cellular oxidative stress. Thioredoxin‐1 (Trx‐1) plays a major role in the regulation of cellular redox balance, with resultant effects on gene expression and cellular responses including cell growth and death. Trx‐1 activity is inhibited by interaction with vitamin D‐upregulated protein‐1 (VDUP‐1). Peroxisome proliferator‐activated receptor gamma (PPARγ) is expressed by human monocyte‐derived macrophages (HMDM) and PPARγ agonism has been reported to decrease expression of inflammatory genes and to promote apoptosis of these cells. To determine whether VDUP‐1 may be involved in regulating the effects of PPARγ agonists in macrophages, we investigated the effect of a synthetic PPARγ agonist (GW929) on the expression of VDUP‐1 in HMDM. GW929 concentration‐dependently increased HMDM expression of VDUP‐1 (mRNA and protein). Transfection of different fragments of the VDUP‐1 promoter as well as gel shift analysis revealed the presence of functional PPARγ response elements (PPRE) in the promoter. Under conditions in which PPAR agonism altered levels of VDUP‐1, caspase‐3 activity, and macrophage apoptosis were also elevated. The results suggest that PPARγ activation stimulates apoptosis in human macrophages by altering the cellular redox balance via regulation of VDUP‐1. J. Cell. Physiol. 214:183–191, 2008. © 2007 Wiley‐Liss, Inc.