Thromboxane A(2) 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 U46619-induced expression of IL-8 was mainly regulated by nuclear factor-kappaB (NF-kappaB). U46619 induced the activation of NF-kappaB through IkappaB kinase (IKK) activation, IkappaB phosphorylation and NF-kappaB 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-kappaB activation in endothelial cells.
Kim
Su-Ryun
SR
School of Dentistry and Research Institute for Oral Biotechnology, Pusan National University, Yangsan 626-870, South Korea.
Bae
Soo-Kyung
SK
Park
Hyun-Joo
HJ
Kim
Mi-Kyoung
MK
Kim
Koanhoi
K
Park
Shi-Young
SY
Jang
Hye-Ock
HO
Yun
Il
I
Kim
Yung-Jin
YJ
Yoo
Mi-Ae
MA
Bae
Moon-Kyoung
MK
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D002199:Capillary Permeability; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000187:drug effects; D021381:Protein Transport; D013928:Thromboxane A2 / Q000378:metabolism*; D015854:Up-Regulation
D020672:I-kappa B Proteins; D016209:Interleukin-8; D016328:NF-kappa B; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid