Enhanced VDUP-1 gene expression by PPARγ agonist induces apoptosis in human mlacrophage
Enhanced VDUP-1 gene expression by PPARγ agonist induces apoptosis in human mlacrophage
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DOI：
10.1002/jcp.21179
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发表时间：
2008-01-01
影响因子：
5.6
通讯作者：
Rouis, M.
中科院分区：
文献类型：
--
作者：
Billiet, L.;Furman, C.;Rouis, M.
病变巨噬细胞的命运和表型受细胞氧化应激调节。硫氧还蛋白-1 (Trx-1) 在细胞氧化还原平衡的调节中发挥着重要作用，从而对基因表达和细胞反应（包括细胞生长和死亡）产生影响。 Trx-1 活性通过与维生素 D 上调蛋白 1 (VDUP-1) 的相互作用而受到抑制。过氧化物酶体增殖物激活受体 γ (PPAR γ) 由人单核细胞源性巨噬细胞 (HMDM) 表达，据报道 PPAR γ 激动剂可减少炎症基因的表达并促进这些细胞的凋亡。为了确定 VDUP-1 是否可能参与调节巨噬细胞中 PPAR γ 激动剂的作用，我们研究了合成 PPAR γ 激动剂 (GW929) 对 HMDM 中 VDUP-1 表达的影响。 GW929 浓度依赖性增加 VDUP-1（mRNA 和蛋白质）的 HMDM 表达。 VDUP-1 启动子不同片段的转染以及凝胶位移分析揭示了启动子中存在功能性 PPAR γ 反应元件 (PPRE)。在 PPAR 激动改变 VDUP-1 水平的条件下，caspase-3 活性和巨噬细胞凋亡也会升高。结果表明，PPAR γ 激活通过调节 VDUP-1 改变细胞氧化还原平衡，从而刺激人巨噬细胞凋亡。
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 (PPAR gamma) is expressed by human monocyte-derived macrophages (HMDM) and PPAR gamma 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 PPAR gamma agonists in macrophages, we investigated the effect of a synthetic PPAR gamma 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 PPAR gamma 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 PPAR gamma activation stimulates apoptosis in human macrophages by altering the cellular redox balance via regulation of VDUP-1.