Activation of thromboxane receptor upregulates interleukin (IL)-1beta-induced VCAM-1 expression through JNK signaling.
OBJECTIVE
Activation of thromboxane receptors (TPr) is implicated in atherosclerosis and inflammation. This study examined how activation of TPr modulates IL-1beta-induced vascular cell adhesion molecule (VCAM)-1 expression in aortic vascular smooth muscle cells (VSMCs).


RESULTS
In VSMCs, activation of TPr with U46619, a stable thromboxane A2 mimetic, alone did not induce VCAM-1 expression, but enhanced that caused by IL-1beta. 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-kappaB activation. Furthermore, U46619 enhanced IL-1beta-induced THP-1 monocyte binding to VSMCs, which was inhibited by SQ29548 or SP600125.


CONCLUSIONS
This study demonstrates that activation of TPr upregulates IL-1beta-induced VCAM-1 expression by enhancing the activation of JNK pathway that leads to enhanced AP-1 activation.
Bayat
Hossein
H
Whitaker Cardiovascular Institute, Vascular Biology Unit, Department of Medicine, Boston University School of Medicine, Mass 02118, USA.
Xu
Shanqin
S
Pimentel
David
D
Cohen
Richard A
RA
Jiang
Bingbing
B
D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology*; D002478:Cells, Cultured; D015777:Eicosanoids / Q000502:physiology; D006801:Humans; D053583:Interleukin-1beta / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D032342:Muscle Cells / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D051381:Rats; D017208:Rats, Wistar; D017482:Receptors, Thromboxane / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000502:physiology; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
D015777:Eicosanoids; D053583:Interleukin-1beta; D017482:Receptors, Thromboxane; D018808:Transcription Factor AP-1; D019010:Vascular Cell Adhesion Molecule-1; D048031:JNK Mitogen-Activated Protein Kinases