Mechanisms and implications of phosphoinositide 3-kinase δ in promoting neutrophil trafficking into inflamed tissue
Mechanisms and implications of phosphoinositide 3-kinase δ in promoting neutrophil trafficking into inflamed tissue
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DOI：
10.1182/blood-2003-05-1667
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发表时间：
2004-05-01
期刊：
影响因子：
20.3
通讯作者：
Diacovo, TG
中科院分区：
文献类型：
--
作者：
Puri, KD;Doggett, TA;Diacovo, TG
磷脂酰肌醇3-激酶(PI3K)催化亚基p110Delta在中性粒细胞中表达，并被认为通过促进趋化物质导向的迁移而在炎症部位聚集。我们在此报道，p110 Delta存在于内皮细胞中，并通过调节这些细胞的前黏附状态来响应肿瘤坏死因子α(TNFpha)而参与中性粒细胞的运输。具体地说，给动物注射选择性PI3K8抑制剂IC87114，可以减少中性粒细胞拴在细胞因子激活的微血管上，并增加其滚动速度，其方式与在p110 Delta缺陷小鼠中观察到的类似。这些结果在体外被证实是抑制内皮细胞中的这种异构体，而不是中性粒细胞，减少了细胞在血流中的附着。IC87114处理PI3KDelta细胞后，Akt-磷酸化和磷脂酰肌醇依赖的激酶1(PDK1)活性降低，证明了PI3KDelta在TNFpha诱导的信号转导中的作用。在中性粒细胞中表达的p110 Delta也有助于运输，这一点在动物体内的炎症小静脉中得到了证明，在这些动物中，这个催化亚单位被阻断或基因缺失，跨井迁移分析证实了这一点。因此，在特定的炎症条件下，PI3K Delta可能是一个合理的治疗靶点，因为阻断其活性可以通过减少中性粒细胞与血管内皮细胞的附着和跨血管内皮细胞的迁移来减少中性粒细胞进入组织的数量。(C)2004年，由美国血液病学会提供。
The phosphoinositide 3-kinase (PI3K) catalytic subunit p110delta is expressed in neutrophils and is thought to play a role in their accumulation at sites of inflammation by contributing to chemoattractant-directed migration. We report here that p110delta is present in endothelial cells and participates in neutrophil trafficking by modulating the proadhesive state of these cells in response to tumor necrosis factor alpha (TNFalpha). Specifically, administration of the selective inhibitor of PI3K8, IC87114, to animals reduced neutrophil tethering to and increased rolling velocities on cytokine-activated microvessels in a manner similar to that observed in mice deficient in p110delta. These results were confirmed in vitro as inhibition of this isoform in endothelium, but not neutrophils, diminished cell attachment in flow. A role for PI3Kdelta in TNFalpha-induced signaling is demonstrated by a reduction in Akt-phosphorylation and phosphatidylinositol-dependent kinase 1 (PDK1) enzyme activity upon treatment of this cell type with IC87114. p110delta expressed in neutrophils also contributes to trafficking as demonstrated by the impaired movement of these cells across inflamed venules in animals in which this catalytic subunit was blocked or genetically deleted, results corroborated in transwell migration assays. Thus, PI3Kdelta may be a reasonable therapeutic target in specific inflammatory conditions as blockade of its activity reduces neutrophil influx into tissues by diminishing their attachment to and migration across vascular endothelium. (C) 2004 by The American Society of Hematology.