Potentiation of neutrophil cyclooxygenase-2 by adenosine: an early anti-inflammatory signal
Potentiation of neutrophil cyclooxygenase-2 by adenosine: an early anti-inflammatory signal
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DOI：
10.1242/jcs.01737
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发表时间：
2005-04-01
影响因子：
4
通讯作者：
Pouliot, M
中科院分区：
文献类型：
--
作者：
Cadieux, JS;Leclerc, P;Pouliot, M
中性粒细胞通常最先在炎症部位迁移，可以通过5-脂氧合酶途径产生白三烯B-4，通过诱导环氧合酶-2途径产生前列腺素E-2。腺苷是一种内源性金盏花素，具有多种抗炎特性，它在激活A(2A)受体后，阻止白三烯B-4的合成，同时增强fMLP治疗的中性粒细胞中的环氧合酶-2途径。利用小鼠气囊炎症模型，我们观察到缺乏A(2A)受体的小鼠的炎性白细胞比野生型动物诱导的环氧合酶-2更少。在人类白细胞中，A(2A)受体的激活特异性地在中性粒细胞中引起环氧合酶-2的增强，但在单核细胞中不能。信号转导研究表明，cAMP、ERK1/2、PI-3K和p38K等细胞内信号转导通路参与了环氧合酶-2的直接上调及其增强。总之，这些结果表明，中性粒细胞是腺苷作用的特别重要的媒介。考虑到在基因敲除小鼠中观察到的不受控制的炎症表型，鉴于前列腺素E-2对炎性细胞的有效抑制作用，A(2A)受体激活导致的环氧合酶-2表达增加，特别是在中性粒细胞中观察到，可能参与了促进腺苷抗炎活性的早期调节机制。
Neutrophils, which are often the first to migrate at inflamed sites, can generate leukotriene B-4 from the 5-lipoxygenase pathway and prostaglandin E-2 through the inducible cyclooxygenase-2 pathway. Adenosine, an endogenous; autacoid with several anti-inflammatory properties, blocks the synthesis of leukotriene B-4 while it potentiates the cyclooxygenase-2 pathway in fMLP-treated neutrophils, following activation of the A(2A) receptor. Using the murine air pouch model of inflammation, we observed that inflammatory leukocytes from mice lacking the A(2A) receptor have less cyclooxygenase-2 induction than wildtype animals. In human leukocytes, A(2A) receptor activation specifically elicited potentiation of cyclooxygenase-2 in neutrophils, but not in monocytes. Signal transduction studies indicated that the cAMP, ERK1/2, PI-3K and p38K intracellular pathways are implicated both in the direct upregulation of cyclooxygenase-2 and in its potentiation. Together, these results indicate that neutrophils are particularly important mediators of adenosine's effects. Given the uncontrolled inflammatory phenotype observed in knockout mice and in view of the potent inhibitory actions of prostaglandin E-2 on inflammatory cells, an increased cyclooxygenase-2 expression resulting from A(2A) receptor activation, observed particularly in neutrophils, may take part in an early modulatory mechanism promoting anti-inflammatory activities of adenosine.