Activation of thromboxane receptor upregulates interleukin (IL)-1β-induced VCAM-1 expression through JNK signaling
Activation of thromboxane receptor upregulates interleukin (IL)-1β-induced VCAM-1 expression through JNK signaling
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DOI：
10.1161/atvbaha.107.150250
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发表时间：
2008-01-01
影响因子：
8.7
通讯作者：
Jiang, Bingbing
中科院分区：
文献类型：
--
作者：
Bayat, Hossein;Xu, Shanqin;Jiang, Bingbing
目的：血栓素受体（TPr）的激活与动脉粥样硬化和炎症有关。本研究探讨了激活TPr如何调节IL-1 β诱导的血管细胞粘附分子(VCAM)-1在主动脉血管平滑肌细胞（VSMCs）中的表达。方法与结果：在VSMCs中，用稳定的血栓素a(2)模拟物U46619单独激活TPr不能诱导VCAM-1表达，但可以增强IL-1 β引起的VCAM-1表达。U46619引起的VCAM-1表达增强发生在转录水平，并被c-Jun n-末端激酶（JNK）抑制剂SP600125或显性阴性JNK1过表达抑制，但不被p38丝裂原激活蛋白激酶抑制剂SB203580抑制。U46619对JNK的激活导致c-Jun磷酸化和核易位增强，并与激活蛋白(AP)-1的激活增强相关，而激活蛋白(AP)-1的激活被TPr拮抗剂SQ29548或JNK抑制剂所消除。单独用U46619处理细胞不诱导NF-kappa B活化。此外，U46619增强了IL-1 β诱导的THP-1单核细胞与VSMCs的结合，而SQ29548或SP600125抑制了这一作用。结论：本研究表明，激活TPr可通过增强JNK通路的激活，从而增强AP-1的激活，从而上调IL-1 β诱导的VCAM-1表达。
Objective-Activation of thromboxane receptors (TPr) is implicated in atherosclerosis and inflammation. This study examined how activation of TPr modulates IL-1 beta-induced vascular cell adhesion molecule (VCAM)-1 expression in aortic vascular smooth muscle cells (VSMCs).Methods and Results-In VSMCs, activation of TPr with U46619, a stable thromboxane A(2) mimetic, alone did not induce VCAM-1 expression, but enhanced that caused by IL-1 beta. The enhancement of VCAM-1 expression caused by U46619 occurred at the transcriptional level and was inhibited either by SP600125, a c-Jun N-terminal kinase (JNK) inhibitor, or by overexpression of a dominant-negative JNK1, but not by SB203580, a p38 mitogen-activated protein kinase inhibitor. The activation of JNK by U46619 resulted in enhanced phosphorylation and nuclear translocation of c-Jun associated with an enhanced activation of activator protein (AP)-1, which were abolished by SQ29548, a TPr antagonist, or the JNK inhibitor. Treatment of the cells with U46619 alone did not induce NF-kappa B activation. Furthermore, U46619 enhanced IL-1 beta-induced THP-1 monocyte binding to VSMCs, which was inhibited by SQ29548 or SP600125.Conclusion-This study demonstrates that activation of TPr upregulates IL-1 beta-induced VCAM-1 expression by enhancing the activation of JNK pathway that leads to enhanced AP-1 activation.