Gene and Protein Responses of Human Monocytes to Extracellular Cysteine Redox Potential
Gene and Protein Responses of Human Monocytes to Extracellular Cysteine Redox Potential
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DOI：
10.1093/toxsci/kfp205
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发表时间：
2009-12-01
影响因子：
3.8
通讯作者：
Jones, Dean P.
中科院分区：
文献类型：
--
作者：
Go, Young-Mi;Craige, Siobhan E.;Jones, Dean P.
血浆中主要巯基/二硫键对半胱氨酸（Cys）及其二硫化物胱氨酸（CySS）（E（h）Cys）的氧化还原电位与氧化应激相关，氧化的E（h）Cys与心血管疾病风险相关。在体外，单核细胞暴露于氧化的E（h）Cys增加促炎细胞因子白细胞介素-1 β（IL-1 β）的表达，表明E（h）Cys可能是氧化应激和慢性炎症之间的机制联系。由于细胞膜含有多种富含Cys的蛋白质，这些蛋白质可能对E（h）Cys敏感，因此我们试图确定E（h）Cys是否特异性影响促炎信号传导或对单核细胞具有其他影响。我们使用微阵列分析和基于质谱的蛋白质组学来评估单核细胞中蛋白质氧化还原状态、基因表达和蛋白质丰度对E（h）Cys的响应的总体变化。途径分析结果显示，除了IL-1 β相关途径外，应激/解毒和细胞死亡途径的组分通过氧化E（h）Cys增加，而细胞生长和增殖途径的组分通过降低的电位增加。表型研究证实，细胞应激反应发生与氧化E-h和细胞增殖刺激减少E-h。因此，血浆E（h）Cys提供了对单核细胞表型的控制，这可能有助于心血管疾病的风险，并为疾病预防提供了新的治疗靶点。
The redox potential of the major thiol/disulfide couple, cysteine (Cys) and its disulfide cystine (CySS), in plasma (E(h)Cys) is oxidized in association with oxidative stress, and oxidized E(h)Cys is associated with cardiovascular disease risk. In vitro exposure of monocytes to oxidized E(h)Cys increases expression of the proinflammatory cytokine, interleukin-1 beta (IL-1 beta), suggesting that E(h)Cys could be a mechanistic link between oxidative stress and chronic inflammation. Because cell membranes contain multiple Cys-rich proteins, which could be sensitive to E(h)Cys, we sought to determine whether E(h)Cys specifically affects proinflammatory signaling or has other effects on monocytes. We used microarray analysis and mass spectrometry-based proteomics to evaluate global changes in protein redox state, gene expression, and protein abundance in monocytes in response to E(h)Cys. Pathway analysis results revealed that in addition to IL-1 beta-related pathways, components of stress/detoxification and cell death pathways were increased by oxidized E(h)Cys, while components of cell growth and proliferation pathways were increased by a reduced potential. Phenotypic studies confirmed that a cell stress response occurred with oxidized E-h and that cell proliferation was stimulated with reduced E-h. Therefore, plasma E(h)Cys provides a control over monocyte phenotype, which could contribute to cardiovascular disease risk and provide a novel therapeutic target for disease prevention.