Role of endothelial heparanase in delayed-type hypersensitivity
Role of endothelial heparanase in delayed-type hypersensitivity
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DOI：
10.1182/blood-2005-08-3301
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发表时间：
2006-05-01
期刊：
影响因子：
20.3
通讯作者：
Elkin, M
中科院分区：
文献类型：
--
作者：
Edovitsky, E;Lerner, I;Elkin, M
乙酰肝素酶是一种内切糖苷酶，其切割硫酸乙酰肝素（HS），基底膜（BM）的主要多糖。HS负责BM完整性和屏障功能。因此，HS在血管内皮下BM中的酶促降解是炎症期间免疫细胞和血浆组分外渗的先决条件。在这里，我们证明了在小鼠耳朵中引发迟发型超敏反应（DTH）后高度协调的局部乙酰肝素酶诱导。通过监测乙酰肝素酶启动子驱动的荧光素酶基因在体内的激活，我们证明乙酰肝素酶转录激活在DTH的早期阶段。我们报告乙酰肝素酶是由DTH相关炎症部位的内皮细胞局部产生的。关键的DTH介质，肿瘤坏死因子-α和干扰素-γ，被发现在培养的内皮细胞中诱导乙酰肝素酶。内皮素作为乙酰肝素酶酶活性的基本细胞来源出现，其反过来允许血管BM的重塑、增加的血管渗透性以及白细胞和血浆蛋白的外渗。体内施用抗乙酰肝素酶siRNA或乙酰肝素酶酶活性抑制剂有效地停止了DTH炎症反应。总的来说，我们的研究结果突出了内皮乙酰肝素酶在DTH炎症中的决定性作用及其作为抗炎药物开发的有前途的靶点的潜力。
Heparanase is an endoglycosidase that cleaves heparan sulfate (HS), the main polysaccharide of the basement membrane (BM). HS is responsible for BM integrity and barrier function. Hence, enzymatic degradation of HS in the vascular subendothelial BM is a prerequisite for extravasation of immune cells and plasma components during inflammation. Here, we demonstrate a highly coordinated local heparanase induction upon elicitation of delayed-type hypersensitivity (DTH) reaction In the mouse ear. By monitoring in vivo activation of luciferase gene driven by the heparanase promoter, we demonstrate activation of heparanase transcription at an early stage of DTH. We report that heparanase is produced locally by the endothelium at the site of DTH-associated inflammation. Key DTH mediators, tumor necrosis factor-alpha and interferon-gamma,were found to induce heparanase in cultured endothelial cells. Endothelium emerges as an essential cellular source of heparanase enzymatic activity that, in turn, allows for remodeling of the vascular BM, increased vessel permeability, and extravasation of leukocytes and plasma proteins. In vivo administration of antiheparanase siRNA or an inhibitor of heparanase enzymatic activity effectively halted DTH inflammatory response. Collectively, our results highlight the decisive role of endothelial heparanase in DTH inflammation and its potential as a promising target for anti-inflammatory drug development.