Opposing effects of platelet-activating factor and lyso-platelet-activating factor on neutrophil and platelet activation.
Opposing effects of platelet-activating factor and lyso-platelet-activating factor on neutrophil and platelet activation.
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DOI：
10.1124/mol.108.051003
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发表时间：
2009-01
影响因子：
3.6
通讯作者：
Ye RD
中科院分区：
文献类型：
--
作者：
Welch EJ;Naikawadi RP;Li Z;Lin P;Ishii S;Shimizu T;Tiruppathi C;Du X;Subbaiah PV;Ye RD
血小板活化因子（PAF）是一种有效的生物活性磷脂，通过其G蛋白偶联受体（GPCR）作用于多种细胞和组织。PAF不储存，而是通过前体lysoPAF的酶促乙酰化快速产生。PAF的生物活性受到PAF乙酰水解酶的有效而严格的调节，其将PAF转化为lysoPAF。以往的研究报道lysoPAF是PAF的无活性前体和代谢产物。然而，lysoPAF尚未在其自身背景下仔细研究。在这里，我们报告说，lysoPAF有一个相反的作用PAF的激活中性粒细胞和血小板。而PAF增强中性粒细胞NADPH氧化酶的激活，lysoPAF剂量依赖性地抑制这一功能。lysoPAF的抑制作用不受PAF受体拮抗剂或PAF受体基因缺失的影响。lysoPAF介导的中性粒细胞抑制机制涉及细胞内cAMP水平升高，腺苷酸环化酶的药理学阻断完全逆转了lysoPAF的抑制作用。此外，lysoPAF增加血小板中的细胞内cAMP水平并抑制凝血酶诱导的血小板聚集，这可以通过抑制PKA来逆转。这些发现确定lysoPAF是一种与PAF功能相反的生物活性脂质，并提出了一种新型的内在调节机制来平衡PAF的有效活性。
Platelet-activating factor (PAF) is a potent, bioactive phospholipid that acts on multiple cells and tissues through its G protein-coupled receptor (GPCR). PAF is not stored, but rapidly generated via enzymatic acetylation of the precursor, lysoPAF. The bioactivity of PAF is effectively and tightly regulated by PAF acetylhydrolases, which convert PAF back to lysoPAF. Previous studies report that lysoPAF is an inactive precursor and metabolite of PAF. However, lysoPAF has not been carefully studied in its own context. Here we report that lysoPAF has an opposing effect of PAF in the activation of neutrophils and platelets. Whereas PAF potentiates neutrophil NADPH oxidase activation, lysoPAF dose-dependently inhibits this function. Inhibition by lysoPAF is not affected by the use of a PAF receptor antagonist or genetic deletion of the PAF receptor gene. The mechanism of lysoPAF-mediated inhibition of neutrophils involves an elevation in the intracellular cAMP level, and pharmacological blockade of adenylyl cyclase completely reverses the inhibitory effect of lysoPAF. In addition, lysoPAF increases intracellular cAMP levels in platelets and inhibits thrombin-induced platelet aggregation, which can be reversed by inhibition of PKA. These findings identify lysoPAF as a bioactive lipid with opposing functions of PAF, and suggest a novel and intrinsic regulatory mechanism for balance of the potent activity of PAF.
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影响因子：
37.8
作者：
Arakawa, H;Qian, JY;Ueno, H
通讯作者：
Ueno, H
影响因子：
20.3
作者：
Li, ZY;Zhang, GY;Du, XP
通讯作者：
Du, XP
在缺乏血小板激活因子受体的小鼠中，对内毒素具有完整敏感性的过敏反应受损。
影响因子：
15.3
作者：
Ishii, S;Kuwaki, T;Nagase, T;Maki, K;Tashiro, F;Sunaga, S;Cao, W H;Kume, K;Fukuchi, Y;Ikuta, K;Miyazaki, J;Kumada, M;Shimizu, T
通讯作者：
Shimizu, T
影响因子：
5
作者：
Fukuda, Y;Kawashima, H;Nakanishi, T
通讯作者：
Nakanishi, T
影响因子：
64.8
作者：
HONDA, Z;NAKAMURA, M;SHIMIZU, T
通讯作者：
SHIMIZU, T