Interleukin-33 induces angiogenesis and vascular permeability through ST2/TRAF6-mediated endothelial nitric oxide production
Interleukin-33 induces angiogenesis and vascular permeability through ST2/TRAF6-mediated endothelial nitric oxide production
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DOI：
10.1182/blood-2009-02-203372
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发表时间：
2009-10-01
期刊：
影响因子：
20.3
通讯作者：
Kwon, Young-Guen
中科院分区：
文献类型：
--
作者：
Choi, Yeon-Sook;Choi, Hyun-Jung;Kwon, Young-Guen
白介素33(IL-33)是IL-1细胞因子家族的一员，是免疫反应和炎症性血管疾病的新调节因子。尽管IL-33及其同源受体ST2似乎在血管细胞中表达，但IL-33在血管系统中的确切作用尚未确定。在这项研究中，我们报道了IL-33作为一种有效的内皮激活剂的新作用，促进血管生成和血管通透性。IL-33促进人内皮细胞的增殖、迁移和形态分化，与体内血管生成增加一致。IL-33还可增加血管内皮细胞的通透性，减少血管内皮-钙粘附素在体外促进的细胞-细胞连接，并导致小鼠皮肤血管渗漏。IL-33的上述作用可被ST2基因敲除所阻断。IL-33与ST2的结合通过TRAF6介导的磷酸化肌苷-3-激酶、Akt和内皮一氧化氮合酶的激活，迅速增加了内皮一氧化氮(NO)的产生。此外，药物或基因阻断内皮细胞NO生成可抑制IL-33诱导的血管生成和血管高通透性。这些数据表明，IL-33通过ST2/TRAF6-Akt-eNOS信号通路刺激内皮细胞产生NO，从而促进血管生成和血管渗漏。这些发现为IL-33在血管生成依赖性和炎症性血管疾病的发病机制中的作用开辟了新的视角。(血。2009；114：3117-3126)
Interleukin-33 (IL-33), a member of the IL-1 cytokine family, is emerging as a new regulator of immune responses and inflammatory vascular diseases. Although IL-33 and its cognate receptor ST2 appear to be expressed in vascular cells, the precise role of IL-33 in the vasculature has not been determined. In this study, we report a novel role of IL-33 as a potent endothelial activator, promoting both angiogenesis and vascular permeability. IL-33 increased proliferation, migration, and morphologic differentiation of human endothelial cells, consistently with increased angiogenesis in vivo. IL-33 also increased endothelial permeability with reduced vascular endothelial-cadherin-facilitated cell-cell junctions in vitro and induced vascular leakage in mouse skin. These effects of IL-33 were blocked by knockdown of ST2. Ligation of IL-33 with ST2 rapidly increased endothelial nitric oxide (NO) production through TRAF6-mediated activation of phosphoinoside-3-kinase, Akt, and endothelial NO synthase. Moreover, pharmacologic or genetic blockage of endothelial NO generation resulted in the inhibition of angiogenesis and vascular hyperpermeability induced by IL-33. These data demonstrate that IL-33 promotes angiogenesis and vascular leakage by stimulating endothelial NO production via the ST2/TRAF6-Akt-eNOS signaling pathway. These findings open new perspectives for the role of IL-33 in the pathogenesis of angiogenesis-dependent and inflammatory vascular diseases. (Blood. 2009; 114: 3117-3126)