Interleukin(IL)-4 promotion of CXCL-8 gene transcription is mediated by ERK1/2 pathway in human pulmonary artery endothelial cells
Interleukin(IL)-4 promotion of CXCL-8 gene transcription is mediated by ERK1/2 pathway in human pulmonary artery endothelial cells
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白细胞介素 (IL)-4 在人肺动脉内皮细胞中通过 ERK1/2 通路介导 CXCL-8 基因转录的促进
DOI：
10.1016/j.molimm.2011.05.003
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发表时间：
2011-09-01
影响因子：
3.6
通讯作者：
Lavoie, Jean-Pierre
中科院分区：
文献类型：
--
作者：
Yang, Dao-Feng;Huang, Hong;Lavoie, Jean-Pierre
白细胞介素-4是过敏性肺部炎症反应的核心，但其对气道嗜酸性粒细胞的作用仍有争议。内皮在炎症过程中调节白细胞募集和迁移中起着关键作用。然而，据报道其对IL-4的反应增加或减少中性粒细胞趋化因子的产生。我们假设这些相互矛盾的发现可能是由于内皮细胞来源的组织和血管的大小。研究了重组人白细胞介素4（rhIL-4）对人脐静脉内皮细胞（HUVECs）、人肺动脉内皮细胞（HPAECs）和人肺微血管内皮细胞（HPMECs）表达趋化因子CXCL-8的影响。使用Boyden室评价细胞上清液对中性粒细胞的化学引诱物性质。用Western印迹和电泳迁移率变动分析（EMSA）研究核因子-κ B（NF-κ B B）和丝裂原活化蛋白激酶（MAPK）在IL-4诱导的HPAEC中的作用。我们证明IL-4可增加HPAECs中CXCL-8的mRNA表达和蛋白产生，但在HUVECs和HPMECs中不增加。IL-4刺激的HAPECs的上清液以剂量依赖性方式显著促进中性粒细胞迁移，并且被CXCL-8抑制剂显著减弱。我们还发现细胞外调节蛋白激酶1/2（extracellularregulatedproteinkinase 1/2，ERK 1/2）可被IL-4激活，而JUN-N-末端蛋白激酶（JNK）和p38 MAPK通路则不被激活。此外，HAPEC中的NF-kappa B-DNA结合活性、I kappa B alpha的磷酸化和p65水平不受rhIL-4的影响。这些发现表明，在响应的微观和宏观EC的IL-4显着的功能差异。ERK 1/2在IL-4诱导的趋化因子活化中起作用，而不是NF-κ B、JNK和p38 MAPK信号传导。我们的研究结果表明，抑制ERK 1/2可能是一个可能的目标气道嗜酸性粒细胞在过敏性肺疾病。(C)2011爱思唯尔有限公司保留所有权利。
Interleukin-4 is central to allergic pulmonary inflammatory responses, but its contribution to airway neutrophilia remains controversial. The endothelium plays a critical role in regulating leukocyte recruitment and migration during inflammation. However, its response to IL-4 is reported to either increase or decrease the production of neutrophil chemotactic factors. We hypothesized that these conflicting findings may be due to the tissue and the size of the vessels from which endothelial cells have been derived. The expression of CXCL-8 by human primary culture umbilical veins endothelial cells (HUVECs), human pulmonary artery endothelial cells (HPAECs), and human pulmonary microvascular endothelial cells (HPMECs) when stimulated with recombinant human IL-4 (rhIL-4) was studied. The chemoattractant property of the cells' supernatants for neutrophils was evaluated using Boyden chambers. The role of the nuclear factor-kappa B (NF-kappa B), and mitogen-activated protein kinases (MAPK) in IL-4-induced HPAECs was studied using Western blotting and electrophoretic mobility shift assay (EMSA). We demonstrated that IL-4 increased the mRNA expression and the protein production of CXCL-8 in HPAECs, but not in HUVECs and HPMECs. The supernatants of HAPECs stimulated by IL-4 significantly promoted neutrophils migration in a dose-dependent manner, and was significantly attenuated by an inhibitor of CXCL-8. We also found that extracellular-regulated protein kinase1/2 (ERK1/2) is activated by IL-4 in HPAECs, but not JUN-N-terminal protein kinase (JNK) or p38 MAPK pathway. Furthermore, NF-kappa B-DNA binding activity, phosphorylation of I kappa B alpha and p65 levels were not affected by rhIL-4 in HAPECs. These findings indicate marked functional differences in the response of micro and macro-ECs to IL-4. ERK1/2, rather than NF-kappa B, JNK and p38 MAPK signaling, plays a role in IL-4 induced chemokine activation. Our results suggest that inhibition of ERK1/2 may be a possible target for airway neutrophilia in allergic lung diseases. (C) 2011 Elsevier Ltd. All rights reserved.