Soluble gC1qR Is an Autocrine Signal That Induces B1R Expression on Endothelial Cells
Soluble gC1qR Is an Autocrine Signal That Induces B1R Expression on Endothelial Cells
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DOI：
10.4049/jimmunol.1302031
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发表时间：
2014-01-01
影响因子：
4.4
通讯作者：
Peerschke, Ellinor I. B.
中科院分区：
文献类型：
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作者：
Ghebrehiwet, Berhane;Ji, Yan;Peerschke, Ellinor I. B.
缓激肽(Bradykinin，BK)是已知的最有效的血管扩张激动剂之一，属于促炎肽激动素家族。BK通过两种G蛋白偶联受体：BK受体1(B1R)和BK受体2(BK受体2)诱导其活性。虽然BK受体2在内皮细胞上有结构性表达，但B1R是由IL-1β诱导的。C1q受体是C1q球状头部的受体(GC1qR)，在BK的生成中起作用，它在活化的内皮细胞上表达，也以可溶性gC1qR(SgC1qR)的形式分泌。由于sgC1qR可以与内皮细胞结合，我们推测它也可能是诱导B1R表达的自分泌/旁分泌信号。在这项研究中，我们证明了gC1qR通过一个由174-180残基组成的高度保守的结构域与内皮细胞结合，这一点通过固相结合分析和去卷积荧光显微镜进行了评估。内皮细胞(24 h，37℃)与sgC1qR孵育后，B1R的表达增强，而缺乏AA 174-180和154-162的gC1qR的作用减弱。SgC1qR与内皮细胞的结合是通过表面结合的纤维蛋白原实现的，并被抗纤维蛋白原抑制。综上所述，我们的数据表明，在炎症部位，sgC1qR可以通过从头合成上调B1R的表达，以及快速转移预先形成的B1R，从而增强血管通透性。
Bradykinin (BK) is one of the most potent vasodilator agonists known and belongs to the kinin family of proinflammatory peptides. BK induces its activity via two G protein-coupled receptors: BK receptor 1 (B1R) and BK receptor 2. Although BK receptor 2 is constitutively expressed on endothelial cells (ECs), B1R is induced by IL-1 beta. The C1q receptor, receptor for the globular heads of C1q (gC1qR), which plays a role in BK generation, is expressed on activated ECs and is also secreted as soluble gC1qR (sgC1qR). Because sgC1qR can bind to ECs, we hypothesized that it may also serve as an autocrine/paracrine signal for the induction of B1R expression. In this study, we show that gC1qR binds to ECs via a highly conserved domain consisting of residues 174-180, as assessed by solid-phase binding assay and deconvolution fluorescence microscopy. Incubation of ECs (24 h, 37 degrees C) with sgC1qR resulted in enhancement of B1R expression, whereas incubation with gC1qR lacking aa 174-180 and 154-162 had a diminished effect. Binding of sgC1qR to ECs was through surface-bound fibrinogen and was inhibited by anti-fibrinogen. In summary, our data suggest that, at sites of inflammation, sgC1qR can enhance vascular permeability by upregulation of B1R expression through de novo synthesis, as well as rapid translocation of preformed B1R.