Adenosine up-regulates cyclooxygenase-2 in human granulocytes:: Impact on the balance of eicosanoid generation
Adenosine up-regulates cyclooxygenase-2 in human granulocytes:: Impact on the balance of eicosanoid generation
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DOI：
10.4049/jimmunol.169.9.5279
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发表时间：
2002-11-01
影响因子：
4.4
通讯作者：
Borgeat, P
中科院分区：
文献类型：
--
作者：
Pouliot, M;Fiset, MÉ;Borgeat, P
多形性中性粒细胞（粒细胞; PMN）通常是向炎性病变迁移以执行宿主防御功能的第一个血细胞。中性粒细胞通过释放几种因子对特定刺激作出反应，并通过5-脂氧合酶和诱导型环氧合酶（考克斯）-2途径产生炎症的脂质介质。鉴于腺苷的抗炎特性和对5-脂氧合酶途径的抑制作用，我们在本研究中讨论了这种自体激素对考克斯-2途径的影响。我们观察到腺苷上调考克斯-2酶和mRNA的表达。腺苷也能增加PGE（2）对外源性花生四烯酸的反应，并与考克斯-2蛋白水平相关。腺苷对考克斯-2的增强作用可以通过药理学增加细胞内cAMP水平来模拟，涉及后者作为腺苷上调考克斯-2的假定第二信使。特异性考克斯-2抑制剂用于证实考克斯-2同种型在受刺激的PMN形成前列腺素类中的主要作用。细胞外腺苷的去除显著地强调了PGE（2）对白三烯B形成的抑制潜力，并在此过程中涉及EP 2受体亚型。因此，腺苷可能通过增加PGE（2）的产生促进自限性调节过程，这可能导致PMN功能抑制。这项研究确定了一个新的方面的抗炎性质的腺苷在白细胞，引入的概念，这种autacoid可能发挥其免疫调节活性的一部分，通过修改平衡的脂质介质所产生的中性粒细胞。
Polymorphonuclear neutrophils (granulocytes; PMNs) are often the first blood cells to migrate toward inflammatory lesions to perform host defense functions. PMNs respond to specific stimuli by releasing several factors and generate lipid mediators of inflammation from the 5-lipoxygenase and the inducible cyclooxygenase (COX)-2 pathways. In view of adenosine's anti-inflammatory properties and suppressive impact on the 5-lipoxygenase pathway, we addressed in this study the impact of this autacoid on the COX-2 pathway. We observed that adenosine up-regulates the expression of the COX-2 enzyme and mRNA. Production of PGE(2) in response to exogenous arachidonic acid was also increased by adenosine and correlated with COX-2 protein levels. The potentiating effect of adenosine on COX-2 could be mimicked by pharmacological increases of intracellular cAMP levels, involving the latter as a putative second messenger for the up-regulation of COX-2 by adenosine. Specific COX-2 inhibitors were used to confirm the predominant role of the COX-2 isoform in the formation of prostanoids by stimulated PMNs. Withdrawal of extracellular adenosine strikingly emphasized the inhibitory potential of PGE(2) on leukotriene B, formation and involved the EP2 receptor subtype in this process. Thus, adenosine may promote a self-limiting regulatory process through the increase of PGE(2) generation, which may result in the inhibition of PMN functions. This study identifies a new aspect of the anti-inflammatory properties of adenosine in leukocytes, introducing the concept that this autacoid may exert its immunomodulatory activities in part by modifying the balance of lipid mediators generated by PMNs.