Human Platelets Utilize Cycloxygenase-1 to Generate Dioxolane A3, a Neutrophil-activating Eicosanoid.
Human Platelets Utilize Cycloxygenase-1 to Generate Dioxolane A3, a Neutrophil-activating Eicosanoid.
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DOI：
10.1074/jbc.m115.700609
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发表时间：
2016-06-24
期刊：
影响因子：
--
通讯作者：
O'Donnell VB
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文献类型：
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作者：
Hinz C;Aldrovandi M;Uhlson C;Marnett LJ;Longhurst HJ;Warner TD;Alam S;Slatter DA;Lauder SN;Allen-Redpath K;Collins PW;Murphy RC;Thomas CP;O'Donnell VB
类二十烷酸是发烧、疼痛和炎症的重要介质，可调节急性和慢性疾病期间的细胞信号传导。我们表明，通过使用脂质组学，凝血酶激活的人血小板产生一种新的类型的类花生酸，既刺激和启动人中性粒细胞整合素（Mac-1）的表达，响应于甲酰甲硫氨酰亮氨酰苯丙氨酸。详细表征提出了二氧戊环结构，8-羟基-9，11-二氧戊环二十碳四烯酸（二氧戊环A3，DXA 3）。在生理活化过程中，血小板从内源性花生四烯酸产生纳克量的脂质，在体外或体内被阿司匹林抑制，涉及环氧合酶-1（考克斯）。对人/鼠血小板的药理学和遗传学研究表明，DXA 3的形成需要蛋白酶激活受体1和4、胞质磷脂酶A2（cPLA 2）、Src酪氨酸激酶、p38 MAPK、磷脂酶C和细胞内钙。从纯化的考克斯异构体和化学氧化产生的数据，我们提出，DXA 3产生的中间体从活性位点释放，然后在C8氧化。总之，一种新的由考克斯-1产生的嗜中性粒细胞活化血小板衍生脂质可以激活或引发人中性粒细胞，表明在先天免疫和急性炎症中的作用。
Eicosanoids are important mediators of fever, pain, and inflammation that modulate cell signaling during acute and chronic disease. We show by using lipidomics that thrombin-activated human platelets generate a new type of eicosanoid that both stimulates and primes human neutrophil integrin (Mac-1) expression, in response to formylmethionylleucylphenylalanine. Detailed characterization proposes a dioxolane structure, 8-hydroxy-9,11-dioxolane eicosatetraenoic acid (dioxolane A3, DXA3). The lipid is generated in nanogram amounts by platelets from endogenous arachidonate during physiological activation, with inhibition by aspirin in vitro or in vivo, implicating cyclooxygenase-1 (COX). Pharmacological and genetic studies on human/murine platelets revealed that DXA3 formation requires protease-activated receptors 1 and 4, cytosolic phospholipase A2 (cPLA2), Src tyrosine kinases, p38 MAPK, phospholipase C, and intracellular calcium. From data generated by purified COX isoforms and chemical oxidation, we propose that DXA3 is generated by release of an intermediate from the active site followed by oxygenation at C8. In summary, a new neutrophil-activating platelet-derived lipid generated by COX-1 is presented that can activate or prime human neutrophils, suggesting a role in innate immunity and acute inflammation.