Virella G, Muñoz J F, Galbraith G M, Gissinger C, Chassereau C, Lopes-Virella M F
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston 29425, USA.
Clin Immunol Immunopathol. 1995 May;75(2):179-89. doi: 10.1006/clin.1995.1069.
Human monocyte-derived macrophages are transformed into foam cells upon incubation with immune complexes containing low-density lipoprotein (LDL-IC), which are internalized predominantly through Fc gamma receptor-mediated phagocytosis. We investigated whether the FcR gamma-mediated ingestion of LDL-IC is associated with functional and metabolic activation of the ingesting cells. As end points we used the assay of released interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF alpha) and the reduction of nitroblue tetrazolium, which measures the respiratory burst. LDL-IC, added to the macrophages in concentrations known to induce intracellular accumulation of cholesterol esters and foam cell transformation, stimulated both the cytokine release and the respiratory burst more efficiently than control immune complexes. Time course studies of cytokine release and mRNA expression suggest that the synthesis and release of these two cytokines is under independent control. TNF alpha was released almost immediately after addition of LDL-IC to the macrophages, coinciding with increased early expression of TNF alpha mRNA, detectable 30 min after stimulation. In contrast, IL-1 beta was only increased in stimulated cell supernatants after 8 hr, and the onset of expression of IL-1 beta mRNA was also delayed in comparison to that of TNF alpha mRNA. We noted wide variations in the amounts of TNF alpha released by monocyte-derived macrophages from different donors. We also found that those macrophages which released higher levels of TNF alpha also took up higher amounts of 125I-labeled LDL, suggesting that the expression of LDL receptors by LDL-IC-stimulated macrophages is somehow linked to the degree of activation of these cells. Experiments using the measurement of the oxidative burst as end point corroborated that LDL-IC cause a general activation of macrophage functions. In conclusion, human macrophages are efficiently activated by LDL-IC, as reflected by the release of IL-1 beta and TNF alpha and by the release of oxygen active radicals. Thus, the presentation of LDL-IC to human macrophages induces a variety of metabolic and functional changes which are likely to contribute, directly or indirectly, to endothelial damage and progression of the atheromatous lesion.
人单核细胞衍生的巨噬细胞在与含有低密度脂蛋白的免疫复合物（LDL-IC）孵育后会转化为泡沫细胞，这些免疫复合物主要通过Fcγ受体介导的吞噬作用被内化。我们研究了FcRγ介导的LDL-IC摄取是否与摄取细胞的功能和代谢激活相关。作为终点指标，我们使用了白细胞介素-1β（IL-1β）和肿瘤坏死因子α（TNFα）释放测定以及硝基蓝四唑还原测定，后者用于测量呼吸爆发。以已知能诱导胆固醇酯细胞内积累和泡沫细胞转化的浓度向巨噬细胞中添加LDL-IC，与对照免疫复合物相比，其更有效地刺激了细胞因子释放和呼吸爆发。细胞因子释放和mRNA表达的时间进程研究表明，这两种细胞因子的合成和释放受到独立控制。将LDL-IC添加到巨噬细胞后，TNFα几乎立即释放，这与TNFα mRNA早期表达增加相吻合，刺激后30分钟即可检测到。相比之下，IL-1β仅在刺激8小时后的细胞上清液中增加，并且与TNFα mRNA相比，IL-1β mRNA的表达起始也延迟了。我们注意到来自不同供体的单核细胞衍生巨噬细胞释放的TNFα量存在很大差异。我们还发现，那些释放较高水平TNFα的巨噬细胞也摄取了较高量的125I标记的LDL，这表明LDL-IC刺激的巨噬细胞中LDL受体的表达与这些细胞的激活程度以某种方式相关。以氧化爆发测量作为终点的实验证实，LDL-IC会引起巨噬细胞功能的全面激活。总之，人巨噬细胞被LDL-IC有效激活，这通过IL-1β和TNFα的释放以及氧活性自由基的释放得以体现。因此，向人巨噬细胞呈现LDL-IC会诱导多种代谢和功能变化，这些变化可能直接或间接地导致内皮损伤和动脉粥样硬化病变的进展。
