A direct role for C1 inhibitor in regulation of leukocyte adhesion
A direct role for C1 inhibitor in regulation of leukocyte adhesion
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DOI：
10.4049/jimmunol.174.10.6462
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发表时间：
2005-05-15
影响因子：
4.4
通讯作者：
Davis, AE
中科院分区：
文献类型：
--
作者：
Cai, SH;Dole, VS;Davis, AE
血浆Cl抑制剂（C1 INH）是补体和接触系统蛋白酶的天然抑制剂。C1 INH缺陷的杂合性导致遗传性血管性水肿，这是由缓激肽介导的。用血浆C1 INH治疗不仅在患有遗传性血管性水肿的患者中有效，而且在多种其他疾病模型中也有效，其中这种治疗伴随着减少的中性粒细胞浸润。其潜在机制主要被解释为抑制补体和接触系统的结果。我们已经证明，C1 INH在其N-连接聚糖上表达唾液酸-路易斯（x）四糖，通过该四糖，C1 INH结合E-和P-选择素并在体外干扰白细胞-内皮细胞粘附。在这里，我们表明，无论是天然C1 INH和反应中心裂解C1 INH显着抑制选择素介导的白细胞粘附在几个体外和体内模型，而N-去糖基化C1 INH失去这样的活动。这些数据支持C1 INH在白细胞-内皮细胞粘附中起直接作用的假设，该活性是由碳水化合物介导的，并且它不依赖于蛋白酶抑制活性。C1 INH直接参与选择素介导的细胞粘附的调节可能是生理抑制炎症的重要机制，并可部分解释其在炎性疾病治疗中的效用。
Plasma Cl inhibitor (C1INH) is a natural inhibitor of complement and contact system proteases. Heterozygosity for C1INH deficiency results in hereditary angioedema, which is mediated by bradykinin. Treatment with plasma C1INH is effective not only in patients with hereditary angioedema, but also in a variety of other disease models, in which such therapy is accompanied by diminished neutrophil infiltration. The underlying mechanism has been explained primarily as a result of the inhibition of the complement and contact systems. We have shown that C1INH expresses the sialyl-Lewis(x) tetrasaccharide on its N-linked glycan, via which it binds to E-and P-selectins and interferes with leukocyte-endothelial adhesion in vitro. Here we show that both native C1INH and reactive center cleaved C1INH significantly inhibit selectin-mediated leukocyte adhesion in several in vitro and in vivo models, whereas N-deglycosylated C1INH loses such activities. The data support the hypothesis that C1INH plays a direct role in leukocyte-endothelial cell adhesion, that the activity is mediated by carbohydrate, and that it is independent of protease inhibitory activity. Direct involvement of C1INH in modulation of selectin-mediated cell adhesion may be an important mechanism in the physiologic suppression of inflammation, and may partially explain its utility in therapy of inflammatory diseases.