Human protein S inhibits the uptake of AcLDL and expression of SR-A through Mer receptor tyrosine kinase in human macrophages
Human protein S inhibits the uptake of AcLDL and expression of SR-A through Mer receptor tyrosine kinase in human macrophages
复制标题
DOI：
10.1182/blood-2008-05-158048
复制
发表时间：
2009-01-01
期刊：
影响因子：
20.3
通讯作者：
Chen, Changyi
中科院分区：
文献类型：
--
作者：
Liao, Dan;Wang, Xinwen;Chen, Changyi
人蛋白S是一种抗凝蛋白。但S蛋白是否能调节巨噬细胞清道夫受体A（macrophagescavengerreceptor A，SR-A）的表达和功能尚不清楚。将人THP-1单核细胞和外周血单核细胞分化为巨噬细胞，然后用生理浓度的人蛋白S处理。我们发现，蛋白S显着减少乙酰化低密度脂蛋白（AcLDL）的吸收和巨噬细胞的结合，并降低细胞内胆固醇酯含量。蛋白S在mRNA和蛋白水平上抑制SR-A的表达。蛋白S主要通过抑制转录因子与巨噬细胞中AP-1启动子元件的结合来降低SR-A启动子活性。此外，人蛋白S可以结合并诱导Mer受体酪氨酸激酶（Mer RTK）的磷酸化。可溶性Mer蛋白或酪氨酸激酶抑制剂除莠霉素A有效地阻断蛋白S对AcLDL摄取的影响。免疫组化分析显示，蛋白S的水平显着增加，在人类动脉粥样硬化动脉。因此，人蛋白S可以通过Mer RTK抑制巨噬细胞中SR-A的表达和活性，表明人蛋白S是巨噬细胞摄取修饰的脂蛋白功能的调节剂。（血。2009; 113：165 - 174）
Human protein S is an anticoagulation protein. However, it is unknown whether protein S could regulate the expression and function of macrophage scavenger receptor A (SR-A) in macrophages. Human THP-1 monocytes and peripheral blood monocytes were differentiated into macrophages and then treated with physiological concentrations of human protein S. We found that protein S significantly reduced acetylated low-density lipoprotein (AcLDL) uptake and binding by macrophages and decreased the intracellular cholesteryl ester content. Protein S suppressed the expression of the SR-A at both mRNA and protein levels. Protein S reduced the SR-A promoter activity primarily through inhibition in the binding of transcription factors to the AP-1 promoter element in macrophages. Furthermore, human protein S could bind and induce phosphorylation of Mer receptor tyrosine kinase (Mer RTK). Soluble Mer protein or tyrosine kinase inhibitor herbimycin A effectively blocked the effects of protein S on AcLDL uptake. Immunohistochemical analysis revealed that the level of protein S was substantially increased in human atherosclerotic arteries. Thus, human protein S can inhibit the expression and activity of SR-A through Mer RTK in macrophages, suggesting that human protein S is a modulator for macrophage functions in uptaking of modified lipoproteins. (Blood. 2009; 113: 165-174)