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Multi-step mechanism for activation of active oxygen-producing system in leukocytes

白细胞活性氧产生系统激活的多步机制

基本信息

批准号：
04454532
负责人：
ISHIBASHI Sadahiko
金额：
$ 3.46万
依托单位：
HIROSHIMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1994
项目状态：
已结题

项目摘要

Mechanism for activation of production of O_2, a primary product among active oxygen metabolites, in polymirphonuclear leukocytes was investigated. It is known that the activation of the producing system, NADPH oxidase, is achieved by an association of membrane factors, such as cytochrome b_<558>, and cytosolic factos, such as p47-phox, p67-phox, rac, etc., but it has not been fully clarified how these proteins are assembled to form the active complex on plasma membranes from the disassemvled resting state. We first observed that membrane perturbation as manifested by transient deporalization and increase in membrane fluidity served as the priming step for the production. We have long been involved in studies to show that production of O_2, was increased in accordance with phosphorylation by PKC and concurrent translocation to cell membranes of a cytosolic 46 kDa protein (equivalent to p47-phox), abd developed the line in this study. It was feasible that introduction of phosphate was a significant step for the ativation and atabilization of NADPH oxidase complex. In fact, treatment with protein phosphatase inhibitor resulted increase in O_2 production. However, amphiphilic acidic compounds, such as arachidonic acid and SDS,induced similar translocation and activation without phosphorylation. Since these compounds cause membrane perturbation and have negative charge, those factors may act synergistically. In conclusion, O_2 production in leukocytes proceeds as through multi-steps and at least two PKC-dependent and-independent ways.

本文探讨了多微核白细胞产生活性氧代谢产物中初级产物O_2的激活机制。已知产生系统NADPH氧化酶的活化是通过膜因子如细胞色素B_<558>和胞质因子如p47-phox、p67-phox、rac等的结合实现的，但是还没有完全阐明这些蛋白质是如何从分解的静止状态组装到质膜上形成活性复合物的。我们首先观察到，表现为瞬时去孔和膜流动性增加的膜扰动作为生产的启动步骤。我们长期以来的研究表明，O_2的产生与PKC的磷酸化和胞浆46 kDa蛋白（相当于p47-phox）向细胞膜的转运一致，并在本研究中建立了该细胞系。磷酸盐的引入是NADPH氧化酶复合物活化和稳定的重要步骤。事实上，蛋白磷酸酶抑制剂处理导致O_2产生增加。然而，两亲性酸性化合物，如花生四烯酸和SDS，诱导类似的易位和激活没有磷酸化。由于这些化合物引起膜扰动并具有负电荷，因此这些因素可能协同作用。白细胞产生O_2的过程是多步骤的，至少有两条PKC依赖和非PKC依赖的途径。