P-Selectin Cross-Links PSGL-1 and Enhances Neutrophil Adhesion to Fibrinogen and ICAM-1 in a Src Kinase-Dependent, but GPCR-Independent Mechanism
P-Selectin Cross-Links PSGL-1 and Enhances Neutrophil Adhesion to Fibrinogen and ICAM-1 in a Src Kinase-Dependent, but GPCR-Independent Mechanism
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DOI：
10.4161/cam.1.3.4984
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发表时间：
2007-07-01
影响因子：
3.2
通讯作者：
Geng, Jian-Guo
中科院分区：
文献类型：
--
作者：
Xu, Tao;Zhang, Lei;Geng, Jian-Guo
内皮和血小板p选择素（CD62P）和白细胞整合素(M) β (2) （CD11bCD18, Mac-1）是宿主防御和先天免疫所必需的细胞粘附分子。在炎症挑战下，p -选择素与PSGL-1 （p -选择素糖蛋白配体-1，CD162）结合介导中性粒细胞滚动，在此过程中，整合素被细胞外刺激激活，在g蛋白偶联受体（GPCR）依赖的机制下形成坚固的粘附。本研究表明，血小板p -选择素、p -选择素受体球蛋白、抗PSGL-1单抗及其F(ab')(2)通过二聚体或多聚体形式的PSGL-1交联，诱导人中性粒细胞与纤维蛋白原（Fg）和细胞间细胞粘附分子-1 （ICAM-1, CD54）的粘附，并引发适度的α (M) β聚集(2)，但可溶性p -选择素和抗PSGL-1 Fab的单体形式没有。有趣的是，p -选择素没有诱导可检测到的白细胞介素-8 （IL-8）分泌（50 ng/ml）来增加中性粒细胞对Fg的粘附。PP2（一种Src激酶抑制剂）可显著抑制p -选择素诱导的中性粒细胞粘附，而百日咳毒素（一种GPCR抑制剂PTX）则不能。活化的血小板也增加了中性粒细胞与纤维蛋白原的结合，并引发了细胞蛋白的酪氨酸磷酸化。我们的研究结果表明，p -选择素诱导的整合素激活（Src激酶依赖）与细胞因子、趋化因子、趋化因子（gpcr依赖）诱导的整合素激活不同，这表明这两种信号转导途径可能共同促进白细胞整合素的最大激活。
Endothelial and platelet P-selectin (CD62P) and leukocyte integrin alpha(M)beta(2) (CD11bCD18, Mac-1) are cell adhesion molecules essential for host defense and innate immunity. Upon inflammatory challenges, P-selectin binds to PSGL-1 (P-selectin glycoprotein ligand-1, CD162) to mediate neutrophil rolling, during which integrins become activated by extracellular stimuli for their firm adhesion in a G-protein coupled receptor (GPCR)-dependent mechanism. Here we show that cross-linking of PSGL-1 by dimeric or multimeric forms of platelet P-selectin, P-selectin receptor-globulin, anti-PSGL-1 mAb and its F(ab')(2) induced adhesion of human neutrophils to fibrinogen (Fg) and intercellular cell adhesion molecule-1 (ICAM-1, CD54) and triggered a moderate clustering of alpha(M)beta(2), but monomeric forms of soluble P-selectin and anti-PSGL-1 Fab did not. Interestingly, P-selectin did not induce a detectable interleukine-8 (IL-8) secretion (50 ng/ml) was required to increase neutrophil adhesion to Fg. P-selectin-induced neutrophil adhesion was significantly inhibited by PP2 (a Src kinase inhibitor), but not by pertussis toxin (PTX; a GPCR inhibitor). Activated platelets also increased neutrophil binding to fibrinogen and triggered tyrosine phosphorylation of cellular proteins. Our results indicate that P-selectin-induced integrin activation (Src kinase-dependent) is distinct from that elicited by cytokines, chemokines, chemoattractants (GPCR-dependent), suggesting that these two signal transduction pathways may cooperate for maximal activation of leukocyte integrins.