Sequential activation of class IB and class IA PI3K is important for the primed respiratory burst of human but not murine neutrophils
Sequential activation of class IB and class IA PI3K is important for the primed respiratory burst of human but not murine neutrophils
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DOI：
10.1182/blood-2005-03-0944
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发表时间：
2005-08-15
期刊：
影响因子：
20.3
通讯作者：
Hawkins, PT
中科院分区：
文献类型：
--
作者：
Condliffe, AM;Davidson, K;Hawkins, PT
众所周知，人中性粒细胞预暴露于促炎细胞因子显著增加了随后刺激的活性氧（ROS）的产生。这种引发事件被认为对于将ROS定位于炎症附近、最大化它们在炎症消退中的作用以及最小化对周围组织的损伤是至关重要的。我们已经使用了新一代的异构体选择性磷酸肌醇3-激酶（PI 3 K）抑制剂，以表明在这些情况下，ROS的生产是由I类PI 3 K活性的时间控制。用N-甲酰基甲硫氨酰-亮氨酰-苯丙氨酸（fMLP）刺激肿瘤坏死因子-α（TNF-alpha）致敏的人中性粒细胞会导致PI 3 K的双相激活;第一阶段很大程度上依赖于PI 3 K γ，第二阶段很大程度上依赖于PI 3 K δ。PI 3 K激活的第二阶段需要第一阶段;正是这个第二阶段被TNF-α引发增强，并调节ROS产生的平行激活。令人惊讶的是，尽管TNF-α致敏的小鼠骨髓来源的中性粒细胞在响应fMLP时表现出表面相似的PI 3 K激活和ROS产生模式，但这些反应要低得多，并且很大程度上依赖于单独的PI 3 K γ。这些结果开始定义哪些PI 3 K亚型负责调节中性粒细胞对感染和炎症的反应。
It is well established that preexposure of human neutrophils to proinflammatory cytokines markedly augments the production of reactive oxygen species (ROS) to subsequent stimuli. This priming event is thought to be critical for localizing ROS to the vicinity of the inflammation, maximizing their role in the resolution of the inflammation, and minimizing the damage to surrounding tissue. We have used a new generation of isoform-selective phosphoinositide 3-kinase (PI3K) inhibitors to show that ROS production under these circumstances is regulated by temporal control of class I PI3K activity. Stimulation of tumor necrosis factor-alpha (TNF-alpha)-primed human neutrophils with N-formylmethionyl-leucyl-phenylalanine (fMLP) results in biphasic activation of PI3K; the first phase is largely dependent on PI3K gamma, and the second phase is largely dependent on PI3K delta. The second phase of PI3K activation requires the first phase; it is this second phase that is augmented by TNF-alpha priming and that regulates parallel activation of ROS production. Surprisingly, although TNF-alpha-primed mouse bone marrow-derived neutrophils exhibit superficially similar patterns of PI3K activation and ROS production in response to fMLP, these responses are substantially lower and largely dependent on PI3K gamma alone. These results start to define which PI3K isoforms are responsible for modulating neutrophil responsiveness to infection and inflammation.