Human endothelial-cell specific molecule-1 binds directly to the integrin CD11a/CD18 (LFA-1) and blocks binding to intercellular adhesion molecule-1
Human endothelial-cell specific molecule-1 binds directly to the integrin CD11a/CD18 (LFA-1) and blocks binding to intercellular adhesion molecule-1
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DOI：
10.4049/jimmunol.167.6.3099
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发表时间：
2001-09-15
影响因子：
4.4
通讯作者：
Lassalle, P
中科院分区：
文献类型：
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作者：
Béchard, D;Scherpereel, A;Lassalle, P
ICAM是LFA-1的配体，LFA-1是参与免疫和炎症过程的单核细胞的主要整合素。我们先前的研究表明，内皮细胞特异性分子-1(ESM-1)是一种由内皮细胞在炎性细胞因子控制下分泌的蛋白多糖。在这里，我们证明了ESM-1与LFA-1直接结合到人血淋巴细胞、单核细胞和Jurkat细胞的细胞表面。ESM-1的结合同样依赖于Ca~(2+)、Mg~(2+)或Mn~(2+)二价离子，它们是特异的、饱和的，对温度敏感。抗CD11a单抗或PMA可引起一过性结合增加，激活后5min达高峰。CD11a和CD18单抗的免疫共沉淀法证实ESM-1与LFA-1整合素直接结合。使用Biacore生物传感器的无细胞系统证实了ESM-1和LFA-1以高亲和力(K-d=18.7 nM)实时动态相互作用。ESM-1以剂量依赖的方式持续抑制可溶性ICAM-1与Jurkat细胞的特异性结合。这些结果表明，ESM-1和ICAM-1与LFA-1在与CD11a的I区非常接近但不同的结合位点上相互作用。通过这一机制，ESM-1可能参与了LFA-1/ICAM-1途径的调节，从而可能影响循环中淋巴细胞向炎症部位的募集和LFA-1依赖的白细胞的黏附和激活。
ICAMs are ligands for LFA-1, a major integrin of mononuclear cells involved in the immune and inflammatory processes. We previously showed that endothelial cell specific molecule-1 (ESM-1) is a proteoglycan secreted by endothelial cells under the control of inflammatory cytokines. Here, we demonstrate that ESM-1 binds directly to LFA-1 onto the cell surface of human blood lymphocytes, monocytes, and Jurkat cells. The binding of ESM-1 was equally dependent on Ca2+, Mg2+, or Mn2+ divalent ions, which are specific, saturable, and sensitive to temperature. An anti-CD11a mAb or PMA induced a transient increase in binding, peaking 5 min after activation. Direct binding of ESM-1 to LFA-1 integrin was demonstrated by specific coimmunoprecipitation by CD11a and CD18 mAbs. A cell-free system using a Biacore biosensor confirmed that ESM-1 and LFA-1 dynamically interacted in real time with high affinity (K-d = 18.7 nM). ESM-1 consistently inhibited the specific binding of soluble ICAM-1 to Jurkat cells in a dose-dependent manner. These results suggest that ESM-1 and ICAM-1 interact with LFA-1 on binding sites very close to but distinct from the I domain of CD11a. Through this mechanism, ESM-1 could be implicated in the regulation of the LFA-1/ICAM-1 pathway and may therefore influence both the recruitment of circulating lymphocytes to inflammatory sites and LFA-1-dependent leukocyte adhesion and activation.