Differential regulation of endothelial cell activation by complement and interleukin 1α
Differential regulation of endothelial cell activation by complement and interleukin 1α
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DOI：
10.1161/01.res.0000216071.87981.16
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发表时间：
2006-03-31
影响因子：
20.1
通讯作者：
Platt, JL
中科院分区：
文献类型：
--
作者：
Brunn, GJ;Saadi, S;Platt, JL
内皮细胞上补体的激活触发促进凝血、血栓形成和炎症的生理变化。与通过许多基因的转录诱导这些变化的激动剂如细胞因子和内毒素不同，补体，特别是膜攻击复合物，主要诱导内皮细胞释放IL-1 α;然后细胞因子可以通过正常血流去除，或者可以以自分泌或旁分泌方式促进内皮细胞反应的全范围活化。我们研究了补体用于激活培养的内皮细胞中白细胞介素（IL）-1 α转录的细胞内信号通路。膜攻击复合物和其他成孔蛋白刺激钙调磷酸酶和激活IL-1 α基因的选择性转录。相反，细胞因子如IL-1 α的作用不是选择性的，也不依赖于钙调磷酸酶活性。IL-1 α的转录，无论是由补体和钙调磷酸酶刺激，还是由“常规激动剂”刺激，如不依赖于钙调磷酸酶的IL-1 α，都是通过核因子κ B转录激活因子与IL-1 α基因启动子的结合进行的。这些发现定义了补体调节内皮细胞产生IL-1 α的分子机制，并解释了血流如何决定补体刺激的炎症程度。
Activation of complement on endothelium triggers physiological changes that promote coagulation, thrombosis, and inflammation. Unlike agonists such as cytokines and endotoxin that induce these changes through transcription of many genes, complement, particularly the membrane attack complex, primarily induces release of IL-1 alpha by the endothelial cells; the cytokine may then be removed by normal blood flow or may promote activation of the full range of endothelial cell responses in an autocrine or paracrine manner. We studied the intracellular signaling pathways used by complement to activate interleukin (IL)-1 alpha transcription in cultured endothelial cells. The membrane attack complex and other pore-forming proteins stimulated calcineurin and activated selective transcription of the IL-1 alpha gene. In contrast, the action of cytokines such as IL-1 alpha was not selective and not dependent on calcineurin activity. Transcription of IL-1 alpha, whether stimulated by complement and calcineurin or by "conventional agonists," such as IL-1 alpha independent of calcineurin, proceeded via binding of nuclear factor kappa B transcriptional activators to the IL-1 alpha gene promoter. These findings define a molecular mechanism through which complement regulates IL-1 alpha production by endothelial cells and explain how blood flow may determine the extent of complement-stimulated inflammation.