G-CSF induced reactive oxygen species involves Lyn-PI3-kinase-Akt and contributes to myeloid cell growth
G-CSF induced reactive oxygen species involves Lyn-PI3-kinase-Akt and contributes to myeloid cell growth
复制标题
DOI：
10.1182/blood-2005-04-1612
复制
发表时间：
2006-03-01
期刊：
影响因子：
20.3
通讯作者：
Corey, SJ
中科院分区：
文献类型：
--
作者：
Zhu, QS;Xia, L;Corey, SJ
粒细胞集落刺激因子（G-CSF）驱动粒细胞的产生、存活、分化和炎症功能。活性氧（ROS）提供了炎症反应的主要推力，尽管过量的ROS可能是有害的。G-CSF刺激显示ROS产生的时间和剂量依赖性增加，与林恩和Akt的激活相关。抑制林恩、PI 3-激酶和Akt可消除G-CSF诱导的ROS产生。这也被DPI阻断，DPI是NADPH氧化酶的特异性抑制剂。在G-CSF刺激后，来自林恩（-/-）小鼠的中性粒细胞产生的ROS少于野生型同窝小鼠。G-CSF诱导NADPH氧化酶亚基p47（phox）的丝氨酸磷酸化和膜转位。由于截短G-CSF受体的患者发生急性髓性白血病（AML）的风险很高，我们假设ROS的失调有助于白血病的发生。表达截短的G-CSF受体的细胞比表达全长受体的细胞产生更多的ROS。在表达截短型受体G-CSFR Delta 715的骨髓来源的中性粒细胞中，G-CSF诱导的ROS产生增强。抗氧化剂N-乙酰-L-半胱氨酸通过抑制AM的活化减少G-CSF诱导的ROS产生和细胞增殖。这些数据表明G-CSF诱导的Lyn-PI 3 K-Akt途径驱动ROS产生。治疗性靶向Lyn-PI 3 K-激酶-Akt级联的一个有益效果是消除ROS产生。
Granulocyte colony-stimulating factor (G-CSF) drives the production, survival, differentiation, and inflammatory functions of granulocytes. Reactive oxygen species (ROSs) provide a major thrust of the inflammatory response, though excessive ROSs may be deleterious. G-CSF stimulation showed a time- and dose-dependent increase in ROS production, correlating with activation of Lyn and Akt. Inhibition of Lyn, PI3-kinase, and Akt abrogated G-CSF-induced ROS production. This was also blocked by DPI, a specific inhibitor of NADPH oxidase. Following G-CSF stimulation, neutrophils from Lyn(-/-) mice produced less ROSs than wild-type littermates. G-CSF induced both serine phosphorylation and membrane translocation of p47(phox), a subunit of NADPH oxidase. Because patients with a truncated G-CSF receptor have a high risk of developing acute myeloid leukemia (AML), we hypothesized that dysregulation of ROSs contributes to leukemogenesis. Cells expressing the truncated G-CSF receptor produced more ROSs than those with the full-length receptor. G-CSF-induced ROS production was enhanced in bone marrow-derived neutrophils expressing G-CSFR Delta 715, a truncated receptor. The antioxidant N-acetyl-L-cysteine diminished G-CSF-induced ROS production and cell proliferation by inhibiting AM activation. These data suggest that the G-CSF-induced Lyn-PI3K-Akt pathway drives ROS production. One beneficial effect of therapeutic targeting of Lyn-PI3K-kinase-Akt cascade is abrogating ROS production.