Phosphoinositide 3-kinase modulation of β3-integrin represents an endogenous "braking" mechanism during neutrophil transmatrix migration
Phosphoinositide 3-kinase modulation of β3-integrin represents an endogenous "braking" mechanism during neutrophil transmatrix migration
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DOI：
10.1182/blood.v97.10.3251
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发表时间：
2001-05-15
期刊：
影响因子：
20.3
通讯作者：
Colgan, SP
中科院分区：
文献类型：
--
作者：
Bruyninckx, WJ;Comerford, KM;Colgan, SP
在炎症发作期间，中性粒细胞（多形核白细胞[PMN]）遇到内皮下基质基质，可能需要额外的信号传导途径作为通过细胞外间隙运动的指示。使用体外内皮和上皮模型，观察到磷酸肌醇3-激酶（PI 3 K）的抑制剂可促进趋化因子刺激的迁移高达8 +/- 0.3倍。随后的研究表明，PMN以类似的方式对含RGD的基质底物产生反应，并且PMN-基质相互作用被针对β（3）-整联蛋白抗体而非β（1）-整联蛋白抗体的抗体有效抑制，并且PI 3 K抑制剂阻断β（3）-整联蛋白依赖性。通过PI 3 K抑制剂对细胞内β（3）-整联蛋白解偶联的生化分析显示β（3）-整联蛋白酪氨酸磷酸化减少，与p72（syk）的结合减少。类似地，p72（syk）抑制剂piceatannol促进PMN跨基质迁移，而HIV-tat肽促进对应于β（3）-整联蛋白细胞质的肽的装载，从而鉴定了该活性的功能性酪氨酸残基。这些数据表明，PI 3 K调节的β（3）-整联蛋白代表了中性粒细胞在通过细胞外基质转运过程中的天然“制动”机制。（血。2001;97：3261-3258）（C）2001由美国血液学学会。
During episodes of inflammation, neutrophils (polymorphonuclear leukocytes [PMNs]) encounter subendothelial matrix substrates that may require additional signaling pathways as directives for movement through the extracellular space. Using an in vitro endothelial and epithelial model, inhibitors of phosphoinositide 3-kinase (PI3K) were observed to promote chemoattractant-stimulated migration by as much as 8 +/- 0.3-fold. Subsequent studies indicated that PMNs respond in a similar manner to RGD-containing matrix substrates and that PMN-matrix interactions are potently inhibited by antibodies directed against beta (3)- but not beta (1)-integrin antibodies, and that PI3K inhibitors block beta (3)-integrin dependence. Biochemical analysis of intracellular beta (3)-integrin uncoupling by PI3K inhibitors revealed diminished beta (3)-integrin tyrosine phosphorylation and decreased association with p72(syk). Similarly, the p72(syk) inhibitor piceatannol promoted PMN transmatrix migration, whereas HIV-tat peptide-facilitated loading of peptides corresponding to the beta (3)-integrin cytoplasmic tall identified the functional tyrosine residues for this activity. These data indicate that PI3K-regulated beta (3)-integrin represents a natural "braking" mechanism for PMNs during transit through the extracellular matrix. (Blood. 2001;97:3261-3258) (C) 2001 by The American Society of Hematology.