CD93 is rapidly shed from the surface of human myeloid cells and the soluble form is detected in human plasma
CD93 is rapidly shed from the surface of human myeloid cells and the soluble form is detected in human plasma
复制标题
DOI：
10.4049/jimmunol.175.2.1239
复制
发表时间：
2005-07-15
影响因子：
4.4
通讯作者：
Tenner, AJ
中科院分区：
文献类型：
--
作者：
Bohlson, SS;Silva, R;Tenner, AJ
CD 93是在单核细胞、中性粒细胞、内皮细胞和干细胞上表达的高度糖基化的跨膜蛋白。针对CD 93的抗体调节吞噬作用，并且CD 93缺陷小鼠在从发炎的腹膜清除凋亡细胞方面有缺陷。在这项研究中，我们观察到，CD 93，表达在人类单核细胞和中性粒细胞，是敏感的佛波醇二丁酸酯诱导的蛋白质胞外域脱落的时间和剂量依赖性的方式。在培养物上清液中发现的可溶性片段保留N-末端碳水化合物。在胞外域切割后，表皮生长因子重复序列识别结构域。重要的是，在人血浆中检测到可溶形式的CD 93胞外域，表明脱落是一种生理学相关过程。用1，10-菲咯啉抑制金属蛋白酶可抑制脱落，但脱落不依赖于TNF-α转化酶（一种去整合素和金属蛋白酶17）。佛波酯二丁酸诱导的单核细胞上的CD 93脱落伴随着表面表达的降低，而中性粒细胞显示表面表达的增加，这表明从中性粒细胞表面脱落的CD 93被细胞内储存的CD 93迅速取代。人单核细胞上的CD 93与固定的抗CD 93 mAb交联引发脱落，如细胞相关的全长CD 93减少伴随着含CD 93细胞内结构域的裂解产物增加所证明的。此外，炎症介质TNF-α和LPS刺激CD 93从单核细胞的胞外域裂解。这些数据表明，CD 93对胞外域脱落敏感，鉴定了触发脱落的多种刺激，并鉴定了人血浆中可溶形式的CD 93和细胞内含有裂解产物的胞内结构域，这些裂解产物可能有助于CD 93的生理作用。
CD93 is a highly glycosylated transmembrane protein expressed on monocytes, neutrophils, endothelial cells, and stem cells. Antibodies directed at CD93 modulate phagocytosis, and CD93-deficient mice are defective in the clearance of apoptotic cells from the inflamed peritoneum. In this study we observe that CD93, expressed on human monocytes and neutrophils, is susceptible to phorbol dibutyrate-induced protein ectodomain shedding in a time- and dose-dependent manner. The soluble fragment found in culture supernatant retains the N-terminal carbohydrate. recognition domain and the epidermal growth factor repeats after ectodomain cleavage. Importantly, a soluble form of the CD93 ectodomain was detected in human plasma, demonstrating that shedding is a physiologically relevant process. Inhibition of metalloproteinases with 1,10-phenanthroline inhibited shedding, but shedding was independent of TNF-alpha-converting enzyme (a disintegrin and metalloproteinase 17). Phorbol dibutyrate-induced CD93 shedding on monocytes was accompanied by decreased surface expression, whereas neutrophils displayed an increase in surface expression, suggesting that CD93 shed from the neutrophil surface was rapidly replaced by CD93 from intracellular stores. Cross-linking CD93 on human monocytes with immobilized anti-CD93 mAbs triggered shedding, as demonstrated by a decrease in cell-associated, full-length CD93 concomitant with an increase in CD93 intracellular domain-containing cleavage products. In addition, the inflammatory mediators, TNF-alpha and LPS, stimulated ectodomain cleavage of CD93 from monocytes. These data demonstrate that CD93 is susceptible to ectodomain shedding, identify multiple stimuli that trigger shedding, and identify both a soluble form of CD93 in human plasma and intracellular domain containing cleavage products within cells that may contribute to the physiologic role of CD93.