Urocortin increased endothelial ICAM1 by cPLA2-dependent NF-κB and PKA pathways in HUVECs.
Urocortin increased endothelial ICAM1 by cPLA2-dependent NF-κB and PKA pathways in HUVECs.
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DOI：
10.1530/jme-13-0182
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发表时间：
2013-12
影响因子：
3.5
通讯作者：
Rong Wan;Yunxin Liu;Li Li-Li;Chao Zhu;Lai Jin;Shengnan Li
中科院分区：
文献类型：
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作者：
Rong Wan;Yunxin Liu;Li Li-Li;Chao Zhu;Lai Jin;Shengnan Li
尿皮质素（Ucn 1）是促肾上腺皮质激素释放激素（CRH）家族的一员，参与炎症反应。细胞间粘附分子1（ICAM 1）的表达增加在炎症和免疫反应中起重要作用。我们以前的研究结果表明，Ucn 1显着增强ICAM 1的表达。然而，其潜在机制仍然未知。本研究的目的是探讨Ucn 1诱导ICAM 1上调的详细机制。在这里，我们的特点是Ucn 1的使用，以调节ICAM 1在人脐静脉内皮细胞（HUVECs）的表达的机制。我们的数据显示，Ucn 1通过CRHR 2（CRHR 2）以时间依赖的方式增加ICAM 1和环氧合酶2（COX 2）的表达。此外，COX 2参与ICAM 1的上调。此外，Ucn 1可以通过CRHR 2和CRHR 1以时间依赖的方式增加胞浆磷脂酶A2（cPLA 2）的表达和磷酸化。此外，cPLA 2的抑制剂吡咯苯酮或siRNA消融衰减的ICAM 1的增加诱导Ucn 1。此外，核因子κB（NF-κB）被激活，表现为核p65 NF-κB表达增加和p65 NF-κB磷酸化，这取决于cPLA 2和CRHR 2的激活。NF-κB抑制剂吡咯烷二硫代氨基甲酸可抑制ICAM 1的升高，但对COX 2无影响。此外，Ucn 1增加了前列腺素E2（PGE 2）的产生，从而进一步激活蛋白激酶A（PKA）-CREB途径依赖于cPLA 2通过CRHR 2。此外，NF-κB磷酸化的增加不受选择性COX 2抑制剂NS-398或PKA抑制剂H89的影响。总之，这些数据表明Ucn 1通过CRHR 2通过cPLA 2-NF-κB和cPLA 2-COX 2-PGE 2-PKA-CREB B途径增加ICAM 1表达。
Urocortin (Ucn1), a member of the corticotrophin-releasing hormone (CRH) family, has been reported to participate in inflammation. The increased expression of intercellular adhesion molecule 1 (ICAM1) plays important roles in inflammation and immune responses. Our previous results demonstrated that Ucn1 significantly enhanced the expression of ICAM1. However, the underlying mechanisms are still unknown. The purpose of this study is to investigate the detailed mechanisms of Ucn1-induced upregulation of ICAM1. Here, we characterized the mechanisms of Ucn1 usage to regulate ICAM1 expression in human umbilical vein endothelial cells (HUVECs). Our data revealed that Ucn1 increased ICAM1 and cyclooxygenase 2 (COX2) expressions in a time-dependent manner via CRH receptor 2 (CRHR2). In addition, COX2 was involved in ICAM1 upregulation. Furthermore, Ucn1 could increase the expression and phosphorylation of cytosolic phospholipases A2 (cPLA2) in a time-dependent manner via CRHR2 and CRHR1. Moreover, ablation of cPLA2 by the inhibitor pyrrophenone or siRNA attenuated the ICAM1 increase induced by Ucn1. In addition, nuclear factor κB (NF-κB) was activated, indicated by the increase in nuclear p65NF-κB expression and phosphorylation of p65NF-κB, depending on cPLA2 and CRHR2 activation. Pyrrolidinedithiocarbamic acid, an inhibitor of NF-κB, abolished the elevation of ICAM1 but not COX2. Also, Ucn1 increased the production of prostaglandin E2 (PGE2) which further activated protein kinase A (PKA)-CREB pathways dependent of cPLA2 via CRHR2. Moreover, the increase in NF-κB phosphorylation was not affected by the selective COX2 inhibitor NS-398 or the PKA inhibitor H89. In conclusion, these data indicate that Ucn1 increase the ICAM1 expression via cPLA2-NF-κB and cPLA2-COX2-PGE2-PKA-CREB pathways by means of CRHR2.