Diminution of signal transducer and activator of transcription 3 signaling inhibits vascular permeability and anaphylaxis.
Diminution of signal transducer and activator of transcription 3 signaling inhibits vascular permeability and anaphylaxis.
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DOI：
10.1016/j.jaci.2015.11.024
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发表时间：
2016-07
期刊：
影响因子：
--
通讯作者：
Milner JD
中科院分区：
文献类型：
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作者：
Hox V;O'Connell MP;Lyons JJ;Sackstein P;Dimaggio T;Jones N;Nelson C;Boehm M;Holland SM;Freeman AF;Tweardy DJ;Olivera A;Metcalfe DD;Milner JD
在IgE介导的速发型超敏反应中，血管内皮细胞对肥大细胞介质的反应是透化的。我们以前已经证明，STAT3突变（常染色体显性高IgE综合征; AD-HIES）的患者和小鼠部分保护过敏反应。进一步研究STAT3促进过敏反应的机制，并确定小分子抑制STAT3是否可以预防过敏反应。使用未受影响和STAT3抑制或遗传功能丧失的样本，我们进行了组胺皮肤点刺试验，研究了STAT3对过敏反应动物模型的贡献，测量了内皮细胞通透性、基因和蛋白质表达以及组胺受体介导的信号传导。虽然小鼠肥大细胞脱粒受STAT3阻断的影响最小，但肥大细胞介导的过敏反应在Stat3突变型AD-HIES小鼠和小分子STAT3抑制的野生型小鼠中减弱。AD-HIES患者的组胺皮肤刺痛反应减弱。来源于AD-HIES患者或用STAT3抑制剂治疗的人脐静脉血管内皮细胞（HUVEC）未能通过Src适当地发出信号或适当地溶解由蛋白质血管内皮（VE）-钙粘蛋白和β-连环蛋白组成的粘附连接。此外，我们发现AD-HIES HUVECS中STAT3靶mir17 - 92表达的减少与抑制Src的PTEN表达增加和调节β-连环蛋白细胞动力学的E2F1表达增加相关。这些数据表明，STAT3依赖性转录活性调节内皮连接的结构和功能动力学的关键组件，从而允许血管通透性。
During IgE-mediated immediate hypersensitivity reactions, vascular endothelial cells permeabilize in response to mast cell mediators. We have previously demonstrated that patients and mice with STAT3 mutations (autosomal dominant-hyper IgE syndrome; AD-HIES) are partially protected from anaphylaxis. To further study the mechanism by which STAT3 contributes to anaphylaxis, and determine whether small molecule inhibition of STAT3 can prevent anaphylaxis. Using unaffected and STAT3-inhibited or genetic loss of function samples, we performed histamine skin prick testing, investigated the contribution of STAT3 to animal models of anaphylaxis, measured endothelial cell permeability, gene and protein expression, and histamine receptor-mediated signaling. While mouse mast cell degranulation was minimally affected by STAT3 blockade, mast cell mediator-induced anaphylaxis was blunted in Stat3 mutant AD-HIES mice and in wild-type mice subjected to small molecule STAT3 inhibition. Histamine skin prick responses were diminished in AD-HIES patients. Human umbilical vein vascular endothelial cells (HUVECs) derived from patients with AD-HIES or treated with a STAT3 inhibitor failed to properly signal through Src or to appropriately dissolute the adherens junctions made up of the proteins vascular endothelial (VE)-cadherin and β-catenin. Further, we found that diminished STAT3-target mir17–92 expression in AD-HIES HUVECS is associated with increased PTEN expression, which inhibits Src, and increased E2F1 expression, which regulates β-catenin cellular dynamics. These data demonstrate that STAT3-dependent transcriptional activity regulates critical components for the architecture and functional dynamics of endothelial junctions thus permitting vascular permeability.