Blockade of class IA phosphoinositide 3-kinase in neutrophils prevents NADPH oxidase activation- and adhesion-dependent inflammation
Blockade of class IA phosphoinositide 3-kinase in neutrophils prevents NADPH oxidase activation- and adhesion-dependent inflammation
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DOI：
10.1074/jbc.m610248200
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发表时间：
2007-03-02
影响因子：
4.8
通讯作者：
Malik, Asrar B.
中科院分区：
文献类型：
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作者：
Gao, Xiao-Pei;Zhu, Xiangdong;Malik, Asrar B.
我们研究了IA类磷酸肌醇3-激酶（PI 3 K）在调节PMN中NADPH氧化酶活化中的作用，以及促炎细胞因子TNF-α诱导的PMN依赖性肺部炎症和微血管损伤的机制。TNF-α刺激PMN导致超氧化物的产生，这依赖于CD 11b/CD 18介导的PMN粘附。此外，TNF-α诱导CD 11b/CD 18与NADPH氧化酶亚基Nox 2（gp 91（phox））和p47（phox）磷酸化的结合，表明NADPH氧化酶活化的CD 11b/CD 18依赖性。用Delta p85蛋白转导野生型PMN，Delta p85蛋白是IA类PI 3 K调节亚基p85 α的显性负性形式，与HIV-TAT融合（TAT-Delta p85）阻止了（i）CD 11b/CD 18依赖性PMN粘附，（ii）CD 11b/CD 18与Nox 2的相互作用和p47（phox）的磷酸化，以及（iii）PMN氧化剂的产生。此外，在小鼠中的研究显示，静脉内输达特Delta p85显著减少肺中pMN的募集和TNF-α诱导的肺微血管通透性的增加。我们的结论是IA类PI 3 K作为一个节点调节CD 11b/CD 18-整合素依赖的PMN粘附和激活NADPH氧化酶，并导致氧化剂的生产在PMN粘附的网站，并由此产生的肺微血管损伤小鼠。
We examined the role of class IA phosphoinositide 3-kinase (PI3K) in the regulation of activation of NADPH oxidase in PMNs and the mechanism of PMN-dependent lung inflammation and microvessel injury induced by the pro-inflammatory cytokine TNF-alpha. TNF-alpha stimulation of PMNs resulted in superoxide production that was dependent on CD11b/CD18-mediated PMN adhesion. Additionally, TNF-a induced the association of CD11b/CD18 with the NADPH oxidase subunit Nox2 (gp91(phox)) and phosphorylation of p47(phox), indicating the CD11b/CD18 dependence of NADPH oxidase activation. Transduction of wild-type PMNs with Delta p85 protein, a dominant-negative form of the class IA PI3K regulatory subunit, p85 alpha, fused to HIV-TAT (TAT-Delta p85) prevented (i) CD11b/CD18-dependent PMN adhesion, (ii) interaction of CD11b/CD18 with Nox2 and phosphorylation of p47(phox), and (iii) PMN oxidant production. Furthermore, studies in mice showed that i.v. infusion of TAT Delta p85 significantly reduced the recruitment of pMNs in lungs and increase in lung microvascular permeability induced by TNF-a. We conclude that class IA PI3K serves as a nodal point regulating CD11b/CD18-integrin-dependent PMN adhesion and activation of NADPH oxidase, and leads to oxidant production at sites of PMN adhesion, and the resultant lung microvascular injury in mice.