Thromboxane A2 increases endothelial permeability through upregulation of interleukin-8

Thromboxane A(2) (TXA(2)), a major prostanoid formed from prostaglandin H-2 by thromboxane synthase, is involved in the pathogenesis of a variety of vascular diseases. In this study, we report that TXA(2) mimetic U46619 significantly increases the endothelial permeability both in vitro and in vivo. U46619 enhanced the expression and secretion of interleukin-8 (IL-8), a major inducer of vascular permeability, in endothelial cells. Promoter analysis showed that the 1346619-induced expression of IL-8 was mainly regulated by nuclear factor-kappa B (NF-kappa B). 1346619 induced the activation of NF-kappa B through I kappa B kinase (IKK) activation, I kappa B phosphorylation and NF-kappa B nuclear translocation. Furthermore, the inhibition of IL-8 or blockade of the IL-8 receptor attenuated the U46619-induced endothelial cell permeability by modulating the cell-cell junctions. Overall, these results suggest that U46619 promotes vascular permeability through the production of IL-8 via NF-kappa B activation in endothelial cells. (C) 2010 Elsevier Inc. All rights reserved.