Nuclear IL-33 regulates soluble ST2 receptor and IL-6 expression in primary human arterial endothelial cells and is decreased in idiopathic pulmonary arterial hypertension
Nuclear IL-33 regulates soluble ST2 receptor and IL-6 expression in primary human arterial endothelial cells and is decreased in idiopathic pulmonary arterial hypertension
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DOI：
10.1016/j.bbrc.2014.06.111
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发表时间：
2014-08-15
影响因子：
3.1
通讯作者：
Wort, Stephen J.
中科院分区：
文献类型：
--
作者：
Shao, Dongmin;Perros, Frederic;Wort, Stephen J.
特发性肺动脉高压（IPAH）是一种导致右心室衰竭和死亡的无法治愈的疾病，炎症被认为与血管重塑有关。白细胞介素（IL）-33是“alarmin”家族的成员，可以作用于膜ST 2受体或作为核阻遏物来调节炎症。我们发现，使用免疫组织化学，IL-33的表达是核在健康受试者的血管，而核IL-33是显着减少IPAH患者的血管。这与其肺中IL-33 mRNA表达降低相关。相反，在IPAH中IL-33的血清水平没有变化。然而，可溶性形式的ST 2，sST 2的表达在IPAH患者的血清中增强。使用siRNA敲低人内皮细胞（EC）中的IL-33与参与血管重塑的炎性基因（包括IL-6）的选择性调节相关。此外，IL-33敲低显著增加了内皮细胞的sST 2释放。染色质免疫沉淀证明IL-33结合ST 2基因近端和远端启动子中多个推定的同源结构域蛋白结合基序。IL-33与组蛋白甲基转移酶SUV 39 H1（一种转录抑制因子）形成复合物。总之，IL-33调节IL-6和sST 2（一种内源性IL-33抑制剂）在原代人EC中的表达，并可能通过募集转录抑制蛋白在PAH的发病机制中发挥重要作用。(C)2014 Elsevier Inc. All rights reserved.
Idiopathic pulmonary arterial hypertension (IPAH) is an incurable condition leading to right ventricular failure and death and inflammation is postulated to be associated with vascular remodelling. Interleukin (IL)-33, a member of the "alarmin" family can either act on the membrane ST2 receptor or as a nuclear repressor, to regulate inflammation. We show, using immunohistochemistry, that IL-33 expression is nuclear in the vessels of healthy subjects whereas nuclear IL-33 is markedly diminished in the vessels of IPAH patients. This correlates with reduced IL-33 mRNA expression in their lung. In contrast, serum levels of IL-33 are unchanged in IPAH. However, the expression of the soluble form of ST2, sST2, is enhanced in the serum of IPAH patients. Knock-down of IL-33 in human endothelial cells (ECs) using siRNA is associated with selective modulation of inflammatory genes involved in vascular remodelling including IL-6. Additionally, IL-33 knock-down significantly increased sST2 release from ECs. Chromatin immunoprecipitation demonstrated that IL-33 bound multiple putative homeodomain protein binding motifs in the proximal and distal promoters of ST2 genes. IL-33 formed a complex with the histone methyltransferase SUV39H1, a transcriptional repressor. In conclusion, IL-33 regulates the expression of IL-6 and sST2, an endogenous IL-33 inhibitor, in primary human ECs and may play an important role in the pathogenesis of PAH through recruitment of transcriptional repressor proteins. (C) 2014 Elsevier Inc. All rights reserved.