Proteomic Pathway Analysis Reveals Inflammation Increases Myeloid-Derived Suppressor Cell Resistance to Apoptosis
Proteomic Pathway Analysis Reveals Inflammation Increases Myeloid-Derived Suppressor Cell Resistance to Apoptosis
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DOI：
10.1074/mcp.m110.002980
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发表时间：
2011-03-01
影响因子：
7
通讯作者：
Ostrand-Rosenberg, Suzanne
中科院分区：
文献类型：
--
作者：
Chornoguz, Olesya;Grmai, Lydia;Ostrand-Rosenberg, Suzanne
髓源性抑制细胞（MDSC）在癌症患者和动物体内积累，介导全身免疫抑制并阻碍基于免疫的癌症治疗。我们之前已经证明，炎症经常伴随着肿瘤的发生和发展，增加了MDSC的积累速度和抑制效力。为了确定炎症如何增强MDSC水平和活性，我们使用质谱法鉴定了在高度炎症环境中诱导的MDSC产生的蛋白质。蛋白质组学途径分析鉴定出Fas途径和caspase网络蛋白，使我们假设炎症通过增加MDSC对Fas介导的凋亡的抗性来增强MDSC的积累。MS的发现得到了生物学研究的验证和扩展。利用活化的caspase 3和caspase 8作为细胞凋亡的指标，流式细胞术、共聚焦显微镜和Western blot分析表明，Fas激动剂处理炎症诱导的MDSC含有较低水平的活化caspase，这表明炎症增强了对Fas介导的细胞凋亡的抵抗。通过Fas激动剂处理的MDSC的生存能力研究证实了对Fas介导的细胞凋亡的抗性。这些结果表明，在荷瘤个体中经常存在的炎症环境可以保护MDSC免受外源性诱导的细胞凋亡，从而使MDSC具有更长的体内半衰期，这可能解释了为什么MDSC在炎症环境中积累得更快，水平更高。中国生物医学工程学报（自然科学版），2011,31(2):444 - 444。
Myeloid-derived suppressor cells (MDSC) accumulate in patients and animals with cancer where they mediate systemic immune suppression and obstruct immune-based cancer therapies. We have previously demonstrated that inflammation, which frequently accompanies tumor onset and progression, increases the rate of accumulation and the suppressive potency of MDSC. To determine how inflammation enhances MDSC levels and activity we used mass spectrometry to identify proteins produced by MDSC induced in highly inflammatory settings. Proteomic pathway analysis identified the Fas pathway and caspase network proteins, leading us to hypothesize that inflammation enhances MDSC accumulation by increasing MDSC resistance to Fas-mediated apoptosis. The MS findings were validated and extended by biological studies. Using activated caspase 3 and caspase 8 as indicators of apoptosis, flow cytometry, confocal microscopy, and Western blot analyses demonstrated that inflammation-induced MDSC treated with a Fas agonist contain lower levels of activated caspases, suggesting that inflammation enhances resistance to Fas-mediated apoptosis. Resistance to Fas-mediated apoptosis was confirmed by viability studies of MDSC treated with a Fas agonist. These results suggest that an inflammatory environment, which is frequently present in tumor-bearing individuals, protects MDSC against extrinsic-induced apoptosis resulting in MDSC with a longer in vivo half-life, and may explain why MDSC accumulate more rapidly and to higher levels in inflammatory settings. Molecular & Cellular Proteomics 10: 10.1074/mcp.M110.002980, 1-9, 2011.