Fialkow L, Chan C K, Grinstein S, Downey G P
Department of Medicine, University of Toronto, Ontario, Canada.
J Biol Chem. 1993 Aug 15;268(23):17131-7.
Neutrophils possess a multicomponent NADPH-oxidase that produces large quantities of superoxide, which can in turn generate other reactive oxygen intermediates. Superoxide and its dismutation product, hydrogen peroxide, are powerful oxidants. Because the activity of certain tyrosine kinases and phosphatases can be affected by their redox state, we considered the possibility that endogenously generated reactive oxygen intermediates (ROI) may alter phosphotyrosine formation and thereby function as intra- or intercellular messengers in neutrophils. Exposure of human neutrophils to exogenous oxidants such as diamide induced marked tyrosine phosphorylation of several cellular proteins. More importantly, activation of the NADPH oxidase in permeabilized neutrophils, by direct stimulation of GTP-binding proteins, also resulted in enhanced tyrosine phosphorylation. The latter was NADPH-dependent, paralleled by production of superoxide, and was inhibited by diphenylene iodonium, an inhibitor of the flavoprotein component of the oxidase. Neutrophils, from a patient with chronic granulomatous disease, which are deficient in the production of ROI, demonstrated no such phosphotyrosine accumulation. We conclude that ROI produced by the NADPH oxidase can regulate tyrosine phosphorylation in granulocytes, possibly by effects of oxidation-sensitive tyrosine kinases and/or phosphatases.
中性粒细胞拥有一种多组分的NADPH氧化酶，该酶可产生大量超氧化物，超氧化物进而又能生成其他活性氧中间体。超氧化物及其歧化产物过氧化氢都是强氧化剂。由于某些酪氨酸激酶和磷酸酶的活性会受其氧化还原状态的影响，我们推测内源性生成的活性氧中间体（ROI）可能会改变磷酸酪氨酸的形成，从而在中性粒细胞中作为细胞内或细胞间信使发挥作用。将人类中性粒细胞暴露于外源性氧化剂如二酰胺中，会诱导几种细胞蛋白发生显著的酪氨酸磷酸化。更重要的是，通过直接刺激GTP结合蛋白来激活透化中性粒细胞中的NADPH氧化酶，也会导致酪氨酸磷酸化增强。后者依赖于NADPH，与超氧化物的产生平行，并且被氧化酶黄素蛋白组分的抑制剂二苯碘鎓所抑制。来自慢性肉芽肿病患者的中性粒细胞缺乏ROI的产生，未表现出这种磷酸酪氨酸的积累。我们得出结论，NADPH氧化酶产生的ROI可能通过氧化敏感的酪氨酸激酶和/或磷酸酶的作用来调节粒细胞中的酪氨酸磷酸化。
