Involvement of growth differentiation factor-15/macrophage inhibitory cytokine-1 (GDF-15/MIC-1) in oxLDL-induced apoptosis of human macrophages in vitro and in arteriosclerotic lesions
Involvement of growth differentiation factor-15/macrophage inhibitory cytokine-1 (GDF-15/MIC-1) in oxLDL-induced apoptosis of human macrophages in vitro and in arteriosclerotic lesions
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DOI：
10.1007/s00441-004-0986-3
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发表时间：
2004-11-01
影响因子：
3.6
通讯作者：
Kinscherf, R
中科院分区：
文献类型：
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作者：
Schlittenhardt, D;Schober, A;Kinscherf, R
生长分化因子-15/巨噬细胞抑制性细胞因子-1（GDF-15/MIC-1）是转化生长因子β（TGF-β）超家族的新成员，最近在活化的巨噬细胞（MPhi）中发现。我们现在已经研究了GDF-15/MIC-1在体外和动脉粥样硬化颈动脉中暴露于氧化低密度脂蛋白（oxLDL）相关介质后的人MPhi中的作用。使用RT-PCR和蛋白质印迹法，在培养的人MPhi中发现oxLDL、C-6-神经酰胺、肿瘤坏死因子（TNF α）和过氧化氢（H2 O2）对GDF-15/MIC-1表达的显著诱导。在11例人颈动脉中，计算机辅助形态计量学和回归分析支持的免疫组织化学分析表明，GDF-15/MIC-1免疫反应（IR）与oxLDL IR和锰超氧化物歧化酶（MnSOD）IR在CD 68免疫反应（ir）MPhi中显著共定位，它们也表达AIF-IR。我们的数据表明，GDF-15/MIC-1在人MPhi中是由oxLDL及其介体体外诱导的，并且被认为有助于动脉粥样硬化斑块中的氧化应激依赖性后果，例如调节活化的MPhi中的细胞凋亡和炎症过程。
Growth differentiation factor-15/macrophage inhibitory cytokine-1 (GDF-15/MIC-1) is a new member of the transforming growth factor beta (TGF-beta) superfamily, which has most recently been found in activated macrophages (MPhi). We have now investigated GDF-15/MIC-1 in human MPhi after exposure to oxidized low-density lipoproteins (oxLDL) related mediators in vitro and in arteriosclerotic carotid arteries. Using RT-PCR and Western blotting a pronounced induction of GDF-15/MIC-1 expression by oxLDL, C-6-ceramide, tumor necrosis factor (TNFalpha) and hydrogen peroxide (H2O2) was found in cultured human MPhi. In 11 human arteriosclerotic carotid arteries, immunohistochemical analyses supported by computer-assisted morphometry and regression analyses demonstrated a significant colocalization of GDF-15/MIC-1 immunoreactivity (IR) with oxLDL IR and manganese superoxide dismutase (MnSOD) IR in CD68 immunoreactive (ir) MPhi, which were also expressing AIF-IR (apoptosis-inducing factor), caspase-3-IR (CPP32), PARP-IR, c-Jun/AP-1-IR and p53-IR. Our data suggest that GDF-15/MIC-1 is inducible in human MPhi by oxLDL and its mediators in vitro and is supposed to contribute to oxidative stress dependent consequences in arteriosclerotic plaques, e.g. modulating apoptosis and inflammatory processes in activated MPhi.