Activation of Thromboxane Receptor Upregulates Interleukin (IL)-1β–Induced VCAM-1 Expression Through JNK Signaling

Abstract

Objective— Activation of thromboxane receptors (TPr) is implicated in atherosclerosis and inflammation. This study examined how activation of TPr modulates IL-1β–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-1β. 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-κB activation. Furthermore, U46619 enhanced IL-1β–induced THP-1 monocyte binding to VSMCs, which was inhibited by SQ29548 or SP600125. Conclusion— This study demonstrates that activation of TPr upregulates IL-1β–induced VCAM-1 expression by enhancing the activation of JNK pathway that leads to enhanced AP-1 activation.