Investigation of neutrophil signal transduction using a specific inhibitor of phosphatidylinositol 3-kinase.
Investigation of neutrophil signal transduction using a specific inhibitor of phosphatidylinositol 3-kinase.
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DOI：
10.4049/jimmunol.154.5.2413
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发表时间：
1995-03
影响因子：
4.4
通讯作者：
C. Vlahos;W. Matter;R. F. Brown;A. Traynor-Kaplan;P. Heyworth;E. Prossnitz;R. Ye;P. Marder;J. Schelm;K. J. Rothfuss
中科院分区：
文献类型：
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作者：
C. Vlahos;W. Matter;R. F. Brown;A. Traynor-Kaplan;P. Heyworth;E. Prossnitz;R. Ye;P. Marder;J. Schelm;K. J. Rothfuss
中性粒细胞含有一个多组分的NADPH氧化酶系统，该系统参与了杀菌氧化剂的产生。用FMLP多肽刺激人中性粒细胞，激活这种呼吸爆发酶产生超氧化物，也被证明导致磷脂酰肌醇(Ptdlns)3-激酶的激活。用2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one(LY294002)处理中性粒细胞，可完全抑制Ptdlns 3-激酶的活性，并抑制悬浮的中性粒细胞中超氧化物的产生；FMLP刺激的贴壁细胞的氧化产物的产生也被取消。用PMA处理人中性粒细胞可产生超氧化物，而不激活Ptdlns 3-激酶；LY294002不能阻止暴露于PMA的中性粒细胞产生超氧化物。此外，LY294002不抑制游离NADPH氧化酶的激活、CD11b依赖的黏附、FMLP或FMLP诱导的钙离子通量引起的肌动蛋白聚合。这些结果表明，FMLP受体的信号转导途径涉及Ptdlns3-激酶的激活，这是趋化肽诱导随后的超氧化物产生所必需的。此外，Ptdlns 3-激酶可能直接位于蛋白激酶C或其他蛋白激酶的上游，进而激活NADPH氧化酶系统。
Neutrophils contain a multicomponent NADPH oxidase system that is involved in the production of microbicidal oxidants. Stimulation of human neutrophils with the peptide FMLP activates this respiratory burst enzyme to produce superoxide and also has been shown to result in activation of phosphatidylinositol (Ptdlns) 3-kinase. Treatment of human neutrophils with 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), a potent and specific inhibitor of Ptdlns 3-kinase, resulted in complete inhibition of Ptdlns 3-kinase activity as well as in inhibition of superoxide production in FMLP-treated neutrophils in suspension; FMLP-stimulated oxidant production in adherent cells was also abolished. Treatment of human neutrophils with PMA resulted in production of superoxide without activation of Ptdlns 3-kinase; LY294002 did not block superoxide production in neutrophils exposed to PMA. In addition, LY294002 did not inhibit cellfree NADPH oxidase activation, CD11b-dependent adhesion, actin polymerization in response to FMLP, or FMLP-induced calcium flux. These results suggest that the signal transduction pathway of the FMLP-receptor involves activation of Ptdlns 3-kinase, which is required for subsequent superoxide production induced by the chemotactic peptide. Furthermore, Ptdlns 3-kinase may be located directly upstream of protein kinase C or other protein kinases, which in turn activate the NADPH oxidase system.