Expression and regulation of the metalloproteinase ADAM-8 during human neutrophil pathophysiological activation and its catalytic activity on L-selectin shedding
Expression and regulation of the metalloproteinase ADAM-8 during human neutrophil pathophysiological activation and its catalytic activity on L-selectin shedding
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DOI：
10.4049/jimmunol.178.12.8053
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发表时间：
2007-06-15
影响因子：
4.4
通讯作者：
Diaz-Gonzalez, Federico
中科院分区：
文献类型：
--
作者：
Gomez-Gaviro, Maria;Dominguez-Luis, Maria;Diaz-Gonzalez, Federico
去整合素和金属蛋白酶结构域(ADAM)蛋白是一个跨膜糖蛋白家族，具有异质性表达谱和蛋白水解性、细胞粘附性、融合性和信号转导特性。它的成员之一ADAM-8由多种细胞类型表达，包括神经元、破骨细胞和白细胞，尽管它参与了破骨细胞的形成和神经退变过程，但对其在免疫细胞中的作用知之甚少。在这项研究中，我们发现ADAM-8存在于人中性粒细胞的细胞表面和细胞内颗粒中。在体外，中性粒细胞被激活后，ADAM-8被从颗粒动员到质膜，在那里它通过依赖于金属蛋白酶的脱落机制被释放。静息的中性粒细胞与人内皮细胞的黏附也导致ADAM-8表面表达上调。活动期类风湿关节炎患者滑液中分离的中性粒细胞表达的ADAM-8高于外周血中的中性粒细胞，滑液中可溶性ADAM-8的浓度与关节炎症程度直接相关。值得注意的是，ADAM-8在细胞表面和悬液中的存在增加了哺乳动物细胞中膜结合的L-选择素的胞外结构域脱落。所有这些数据支持ADAM-8在炎症反应中中性粒细胞功能中的潜在相关作用。
A disintegrin and metalloproteinase domain (ADAM) proteins are a family of transmembrane glycoproteins with heterogeneous expression profiles and proteolytic, cell-adhesion, -fusion, and -signaling properties. One of its members, ADAM-8, is expressed by several cell types including neurons, osteoclasts, and leukocytes and, although it has been implicated in osteoclastogenesis and neurodegenerative processes, little is known about its role in immune cells. In this study, we show that ADAM-8 is constitutively present both on the cell surface and in intracellular granules of human neutrophils. Upon in vitro neutrophil activation, ADAM-8 was mobilized from the granules to the plasma membrane, where it was released through a metalloproteinase-dependent shedding mechanism. Adhesion of resting neutrophils to human endothelial cells also led to up-regulation of ADAM-8 surface expression. Neutrophils isolated from the synovial fluid of patients with active rheumatoid arthritis expressed higher amounts of ADAM-8 than neutrophils isolated from peripheral blood and the concentration of soluble ADAM-8 in synovial fluid directly correlated with the degree of joint inflammation. Remarkably, the presence of ADAM-8 both on the cell surface and in suspension increased the ectodomain shedding of membrane-bound L-selectin in mammalian cells. All these data support a potential relevant role for ADAM-8 in the function of neutrophils during inflammatory response.