Cho Hyung Jun, Shashkin Pavel, Gleissner Christian A, Dunson Dane, Jain Nitin, Lee Jae K, Miller Yury, Ley Klaus
Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia 22908, USA.
Physiol Genomics. 2007 Apr 24;29(2):149-60. doi: 10.1152/physiolgenomics.00051.2006. Epub 2007 Jan 23.
Foam cell formation from monocyte-derived macrophages is a hallmark of atherosclerotic lesions. Aspects of this process can be recapitulated in vitro by exposing M-CSF-induced or platelet factor 4 (CXCL4)-induced macrophages to oxidized (ox) or minimally modified (mm) low density lipoprotein (LDL). We measured gene expression in peripheral blood mononuclear cells, monocytes, and macrophages treated with CXCL1 (GRO-alpha) or CCL2 (MCP-1), as well as foam cells induced by native LDL, mmLDL, or oxLDL using 22 Affymetrix gene chips. Using an advanced Bayesian error-pooling approach and a heterogeneous error model with a false discovery rate <0.05, we found 5,303 of 22,215 probe sets to be significantly regulated in at least one of the conditions. Among a subset of 917 candidate genes that were preselected for their known biological functions in macrophage foam-cell differentiation, we found that 290 genes met the above statistical criteria for significant differential expression patterns. While many expected genes were found to be upregulated by LDL and oxLDL, very few were induced by mmLDL. We also found induction of unexpected genes, most strikingly MHC-II and other dendritic cell markers such as CD11c. The gene expression patterns in response to oxLDL were similar in M-CSF-induced and CXCL4-induced macrophages. Our findings suggest that LDL and oxLDL, but not mmLDL, induce a dendritic cell-like phenotype in macrophages, suggesting that these cells may be able to present antigens and support an immune response.
单核细胞衍生的巨噬细胞形成泡沫细胞是动脉粥样硬化病变的一个标志。通过将M-CSF诱导的或血小板因子4（CXCL4）诱导的巨噬细胞暴露于氧化（ox）或轻度修饰（mm）的低密度脂蛋白（LDL），可以在体外重现这一过程的各个方面。我们使用22个Affymetrix基因芯片测量了用CXCL1（GRO-α）或CCL2（MCP-1）处理的外周血单核细胞、单核细胞和巨噬细胞以及由天然LDL、mmLDL或oxLDL诱导的泡沫细胞中的基因表达。使用先进的贝叶斯误差合并方法和错误发现率<0.05的异质误差模型，我们发现在22,215个探针集中有5,303个在至少一种条件下受到显著调节。在917个因其在巨噬细胞泡沫细胞分化中已知的生物学功能而预先选择的候选基因子集中，我们发现有290个基因符合上述显著差异表达模式的统计标准。虽然发现许多预期基因被LDL和oxLDL上调，但很少有基因被mmLDL诱导。我们还发现了意外基因的诱导，最显著的是MHC-II和其他树突状细胞标志物，如CD11c。在M-CSF诱导的和CXCL4诱导的巨噬细胞中，对oxLDL的基因表达模式相似。我们的研究结果表明，LDL和oxLDL而非mmLDL在巨噬细胞中诱导出树突状细胞样表型，这表明这些细胞可能能够呈递抗原并支持免疫反应。
