Lalor Patricia F, Edwards Sarah, McNab Gillian, Salmi Marko, Jalkanen Sirpa, Adams David H
Liver Research Laboratories, University of Birmingham Institute of Clinical Science, Medical Research Council Center for Immune Regulation, Edgbaston, Birmingham, United Kingdom.
J Immunol. 2002 Jul 15;169(2):983-92. doi: 10.4049/jimmunol.169.2.983.
Vascular adhesion protein-1 (VAP-1) is an amine oxidase and adhesion receptor that is expressed by endothelium in the human liver. The hepatic sinusoids are perfused by blood at low flow rates, and sinusoidal endothelium lacks selectin expression and has low levels of CD31, suggesting that VAP-1 may play a specific role in lymphocyte recruitment to the liver. In support of this we now report the constitutive expression of VAP-1 on human hepatic sinusoidal endothelial cells (HSEC) in vitro and demonstrate that VAP-1 supports adhesion and transmigration of lymphocytes across these cells under physiological shear stress. These are the first studies to report the function of VAP-1 on primary human endothelial cells. Under static conditions lymphocyte adhesion to unstimulated HSEC was dependent on VAP-1 and ICAM-2, whereas adhesion to TNF-alpha-stimulated HSEC was dependent on ICAM-1, VCAM-1, and VAP-1. Under conditions of flow, blocking VAP-1 reduced lymphocyte adhesion to TNF-alpha-treated HSEC by 50% and significantly reduced the proportion of adherent lymphocytes that transmigrated across cytokine or LPS-activated endothelium. In addition, inhibition of the amine oxidase activity of VAP-1 reduced both adhesion and transmigration of lymphocytes to a level similar to that seen with VAP-1 Ab. Thus, VAP-1 can support transendothelial migration as well as adhesion, and both functions are dependent on its enzymatic activity. In the absence of selectins and CD31, VAP-1 may play a specific role in lymphocyte recruitment via hepatic sinusoidal endothelium. Moreover, since VAP-1 is induced on nonhepatic endothelium in response to inflammation, its ability to support lymphocyte transendothelial migration may be an important systemic function of VAP-1.
血管黏附蛋白-1（VAP-1）是一种胺氧化酶和黏附受体，由人肝脏中的内皮细胞表达。肝血窦以低流速灌注血液，窦状内皮细胞缺乏选择素表达且CD31水平较低，这表明VAP-1可能在淋巴细胞募集到肝脏过程中发挥特定作用。为此，我们现在报告VAP-1在人肝窦状内皮细胞（HSEC）上的组成性表达，并证明VAP-1在生理剪切应力下支持淋巴细胞黏附和跨这些细胞的迁移。这些是首次报道VAP-1在原代人内皮细胞上功能的研究。在静态条件下，淋巴细胞对未刺激的HSEC的黏附依赖于VAP-1和ICAM-2，而对TNF-α刺激的HSEC的黏附依赖于ICAM-1、VCAM-1和VAP-1。在流动条件下，阻断VAP-1可使淋巴细胞对TNF-α处理的HSEC的黏附减少50%，并显著降低跨细胞因子或LPS激活的内皮细胞迁移的黏附淋巴细胞比例。此外，抑制VAP-1的胺氧化酶活性可将淋巴细胞的黏附和迁移降低到与VAP-1抗体处理相似的水平。因此，VAP-1可支持跨内皮迁移以及黏附，且这两种功能均依赖于其酶活性。在缺乏选择素和CD31的情况下，VAP-1可能在通过肝窦状内皮细胞的淋巴细胞募集中发挥特定作用。此外，由于VAP-1在非肝内皮细胞上因炎症而被诱导，其支持淋巴细胞跨内皮迁移的能力可能是VAP-1的一项重要全身性功能。
