STRUCTURAL RECOGNITION OF A NOVEL FIBRINOGEN GAMMA-CHAIN SEQUENCE(117-133) BY INTERCELLULAR-ADHESION MOLECULE-1 MEDIATES LEUKOCYTE-ENDOTHELIUM INTERACTION
STRUCTURAL RECOGNITION OF A NOVEL FIBRINOGEN GAMMA-CHAIN SEQUENCE(117-133) BY INTERCELLULAR-ADHESION MOLECULE-1 MEDIATES LEUKOCYTE-ENDOTHELIUM INTERACTION
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DOI：
10.1074/jbc.270.2.696
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发表时间：
1995-01-13
影响因子：
4.8
通讯作者：
LANGUINO, LR
中科院分区：
文献类型：
--
作者：
ALTIERI, DC;DUPERRAY, A;LANGUINO, LR
除了在止血方面的作用外，纤维蛋白原还必须在体内启动有效的炎症反应。纤维蛋白原依赖性炎症的分子前提可能在于其与细胞间黏附分子-1(ICAM-1)结合的能力，并通过连接这两种细胞类型来增强单核细胞与内皮细胞的黏附。通过合成肽模拟纤维蛋白原伽马链N(117)NQKIVNLEKVAQLEA(133)，命名为伽马3，可剂量依赖性地抑制I-125纤维蛋白原与内皮细胞或表达ICAM-1的B淋巴母细胞样Daudi细胞的结合(IC50类似于20-40微克/毫升)，从而对新的纤维蛋白原识别的结构和功能进行了表征。相比之下，之前发现的血管细胞纤维蛋白原相互作用序列中没有一个是有效的。在无纤维蛋白原存在的情况下，I-125标记的γ-3可与基因工程细胞ICAM-1特异性结合，但不影响白细胞与内皮细胞的相互作用，但不影响细胞与内皮细胞的黏附。I-125标记的γ-3与未转染的细胞结合，并与ICAM-1结合在细胞因子激活的内皮上，K-d为34mU。与ICAM-1的功能识别一致，固定化的Gamma-3支持JY淋巴母细胞的黏附，并呈剂量依赖关系。我们的结论是，一个新的纤维蛋白原γ3序列N(117)NQKIVNLKEKVAQLEA(133)与ICAM-1结合并调节ICAM-1依赖的黏附。这些发现定义了纤维蛋白原的结构基础：ICAM-1识别，并为抑制纤维蛋白原依赖的炎症反应提供了一个潜在的选择性靶点。
In addition to its role in hemostasis, fibrinogen is obligatorily required to mount competent inflammatory responses in vivo. A molecular prerequisite of fibrinogen-dependent inflammation may reside in its ability to associate with intercellular adhesion molecule-1 (ICAM-1), and enhance monocyte adhesion to endothelium by bridging the two cell types. Structure-function characterization of the novel ICAM-1 recognition of fibrinogen was carried out by synthetic peptidyl mimicry of the fibrinogen gamma chain, A novel peptide sequence, N(117)NQKIVNLKEKVAQLEA(133), designated gamma 3, dose-dependently inhibited (IC50 similar to 20-40 mu g/ml) binding of I-125 fibrinogen to endothelial cells or ICAM-1-expressing B lymphoblastoid Daudi cells. In contrast, none of the previously identified vascular cell fibrinogen interacting sequences was effective. Increasing concentrations of gamma 3 completely inhibited fibrinogen-mediated adhesion of peripheral blood mononuclear cells or vitamin D-3-differentiated monocytic HL-60 cells to endothelium, but did not affect leukocyte-endothelium interaction in the absence of fibrinogen, I-125-Labeled gamma 3 bound specifically and saturably to genetically engineered ICAM-1 transfectants, but not to control non-transfected cells, and associated with ICAM-1 on cytokine-activated endothelium with a K-d of 34 mu M. Consistent with functional recognition of ICAM-1, immobilized gamma 3 supported adhesion of JY lymphoblasts in a dose-dependent reaction inhibited by monoclonal antibodies to ICAM-1. We conclude that a novel fibrinogen gamma 3 sequence N(117)NQKIVNLKEKVAQLEA(133) binds to ICAM-1 and modulates ICAM-1-dependent adhesion. These findings define the structural basis of fibrinogen:ICAM-1 recognition and provide a potential selective target for inhibiting fibrinogen-dependent inflammatory responses.