在流动条件下，人类肥大细胞祖细胞利用α4整合素、血管细胞黏附分子-1（VCAM-1）和P选择素糖蛋白配体-1（PSGL-1）E选择素与人血管内皮进行黏附相互作用。

Human mast cell progenitors use alpha4-integrin, VCAM-1, and PSGL-1 E-selectin for adhesive interactions with human vascular endothelium under flow conditions.

作者信息

Boyce Joshua A, Mellor Elizabeth A, Perkins Brandy, Lim Yaw-Chyn, Luscinskas Francis W

机构信息

Department of Medicine, Harvard Medical School, Boston, MA, USA.

出版信息

Blood. 2002 Apr 15;99(8):2890-6. doi: 10.1182/blood.v99.8.2890.

DOI:10.1182/blood.v99.8.2890

PMID:11929779

Abstract

Mast cells (MCs) are central to asthma and other allergic diseases, and for responses to infection and tissue injuries. MCs arise from committed progenitors (PrMCs) that migrate from the circulation to tissues by incompletely characterized mechanisms, and differentiate in situ in perivascular connective tissues of multiple organs. PrMCs derived in vitro from human cord blood were examined for adhesion molecule expression and their ability to adhere to human umbilical vein endothelial cells (HUVECs) under conditions that mimic physiologic shear flow. The PrMCs expressed alpha(4)beta(1), low levels of beta7, and the beta2-integrins alphaLbeta2 and alphaMbeta2. The PrMCs also expressed PSGL-1, but not L-selectin. At low (0.5 dynes/cm(2)-1.0 dynes/cm(2)) shear stress, PrMCs attached and rolled on recombinant E-selectin and P-selectin and VCAM-1. An anti-PSGL-1 monoclonal antibody (mAb) blocked essentially all adhesion to P-selectin but reduced adhesion to E-selectin by only 40%, suggesting PrMCs express other ligands for E-selectin. PrMCs adhered strongly to tumor necrosis factor-alpha (TNF-alpha)-activated HUVECs, whereas adhesion to interleukin 4 (IL-4)-activated HUVECs was lower. PrMC adhesion to IL-4-activated HUVECs was totally alpha4-integrin- and VCAM-1-dependent. Adhesion to TNF-alpha-activated HUVECs was blocked by 50% by mAbs against alpha4-integrin, vascular cell adhesion molecule-1 (VCAM-1), E-selectin, or PSGL-1, whereas combinations of mAbs to alpha4-integrin plus PSGL-1, or VCAM-1 plus E-selectin, blocked adhesion by greater than 70%. Thus, PrMCs derived in vitro predominantly use alpha4-integrin, VCAM-1, PSGL-1, and other ligands that bind E-selectin for adhesion to cytokine-activated HUVEC monolayers. These observations may explain the abundance of MCs at sites of mucosal inflammation, where VCAM-1 and E-selectin are important inducible receptors.

摘要

肥大细胞（MCs）在哮喘和其他过敏性疾病以及对感染和组织损伤的反应中起核心作用。MCs起源于定向祖细胞（PrMCs），这些祖细胞通过尚未完全明确的机制从循环迁移至组织，并在多个器官的血管周围结缔组织中就地分化。对体外从人脐带血中获得的PrMCs进行检测，观察其在模拟生理剪切流的条件下黏附分子的表达情况以及它们黏附于人脐静脉内皮细胞（HUVECs）的能力。PrMCs表达α(4)β(1)、低水平的β7以及β2整合素αLβ2和αMβ2。PrMCs还表达P选择素糖蛋白配体-1（PSGL-1），但不表达L选择素。在低（0.5达因/平方厘米 - 1.0达因/平方厘米）剪切应力下，PrMCs在重组E选择素、P选择素和血管细胞黏附分子-1（VCAM-1）上附着并滚动。一种抗PSGL-1单克隆抗体（mAb）基本上阻断了与P选择素的所有黏附，但对与E选择素的黏附仅减少了40%，这表明PrMCs表达E选择素的其他配体。PrMCs与肿瘤坏死因子-α（TNF-α）激活的HUVECs强烈黏附，而与白细胞介素4（IL-4）激活的HUVECs的黏附较低。PrMCs与IL-4激活的HUVECs的黏附完全依赖于α4整合素和VCAM-1。针对α4整合素、血管细胞黏附分子-1（VCAM-1）、E选择素或PSGL-1的mAb可使与TNF-α激活的HUVECs的黏附减少50%，而α4整合素加PSGL-1或VCAM-1加E选择素的mAb组合可使黏附减少超过70%。因此，体外获得的PrMCs主要利用α4整合素、VCAM-1、PSGL-1以及其他与E选择素结合的配体黏附于细胞因子激活HUVEC单层。这些观察结果可能解释了在黏膜炎症部位MCs的大量存在，在这些部位VCAM-1和E选择素是重要的诱导性受体。