首页> 外文期刊>Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society >Cytohesin-1 regulates fMLF-mediated activation and functions of the {beta}2 integrin Mac-1 in human neutrophils.
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Cytohesin-1 regulates fMLF-mediated activation and functions of the {beta}2 integrin Mac-1 in human neutrophils.

机译:细胞粘附素-1调节人嗜中性粒细胞中fMLF介导的β2整合素Mac-1的激活和功能。

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The nucleotide exchange factor cytohesin-1 was previously reported to interact with the cytoplasmic domains of the integrin beta-chain common to all beta(2) integrins such as LFA-1 and Mac-1. We show here that cytohesin-1, which contributes to fMLF-induced functional responses in PMNs through activation of Arf6, restrains the activation of the beta(2) integrin Mac-1 (alphaMbeta(2)) in PMNs or dcAMP-differentiated PLB-985 cells. We found that the cytohesin-1 inhibitor SecinH3 or siRNA increased cell adhesion to immobilized fibrinogen and fMLF-mediated conformational changes of Mac-1, monitored using mAb CBRM1/5, specific for the activation epitope of the alphaM subunit. In contrast, PLB-985 cells overexpressing cytohesin-1 showed little adhesion to fibrinogen. The use of SecinH3 and siRNA also revealed that interference with cytohesin-1 signaling also enhanced phagocytosis of zymosan particles and chemotaxis toward fMLF in transwell migration assays. These increments of phagocytosis and chemotaxis in cells treated with SecinH3 and cytohesin-1 siRNA were reversed by a blocking mAb to the integrin-alphaM subunit. We provide evidence for increased polymerized cortical actin in cells treated with SecinH3 and that altered signaling through cytohesin-1 increased cell surface expression of FPRL-1 and impairs the late calcium mobilization response elicited by fMLF. The data provide evidence that stimulation with fMLF initiates a signaling cascade that restrains Mac-1 activation in PMNs. Such crosstalk between FPRL-1 and Mac-1 involves cytohesin-1. We suggest that cytohesin-1 may coordinate activation of the beta(2) integrins to regulate PMN adhesion, phagocytosis, and chemotaxis.
机译:以前据报道核苷酸交换因子cytohesin-1与所有β(2)整合素(如LFA-1和Mac-1)共有的整联蛋白β链的胞质域相互作用。我们在这里显示,通过激活Arf6有助于PMN中fMLF诱导的功能性反应的cytohesin-1抑制了PMN或dcAMP分化的PLB-中的beta(2)整合素Mac-1(alphaMbeta(2))的激活。 985个细胞。我们发现,使用mAb CBRM1 / 5监测的,特异性针对alphaM亚基激活表位的细胞粘附素-1抑制剂SecinH3或siRNA可增加细胞对固定化纤维蛋白原的粘附和fMLF介导的Mac-1构象变化。相反,过表达cytohesin-1的PLB-985细胞对纤维蛋白原的粘附力很小。 SecinH3和siRNA的使用还揭示了对细胞粘附素1信号的干扰还增强了酵母聚糖颗粒的吞噬作用,并在跨孔迁移分析中增强了对fMLF的趋化性。在SecinH3和cytohesin-1 siRNA处理的细胞中,吞噬作用和趋化性的这些增加通过阻断mAb逆转至整合素αM亚基而被逆转。我们为用SecinH3处理的细胞中聚合的皮质肌动蛋白增加提供了证据,并且通过cytohesin-1改变了信号传导,增加了FPRL-1的细胞表面表达,并损害了fMLF引起的晚期钙动员反应。数据提供了证据,表明用fMLF刺激会引发抑制PMN中Mac-1激活的信号级联反应。 FPRL-1和Mac-1之间的这种串扰涉及细胞粘附素1。我们建议,cytohesin-1可能会协调激活beta(2)整合素,以调节PMN粘附,吞噬作用和趋化作用。

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