title: Activation of toll-like receptor 4 modulates vascular endothelial growth factor synthesis through prostacyclin-IP signaling.
abstract: In this study, we show that activation of toll-like receptor (TLR)4 by lipopolysaccharide (LPS) induces cyclooxygenase-2 (COX-2) expression, which results in prostaglandin (PG)I2 formation in macrophages. The LPS-stimulated COX-2 expression and PGI2 release were accompanied by production of the potent angiogenic cytokine, vascular endothelial growth factor (VEGF), and these effects were suppressed by NS-398, which is a COX-2 inhibitor. Direct addition of iloprost (an analogue of PGI2) for IP receptor also induced the production of VEGF, whereas DP, FP, and TP receptor agonists did not. Inhibition of IP protein expression by micro interfering RNA blocked LPS-induced VEGF production. Additionally, macrophages transiently caused Akt phosphorylation after stimulation with LPS, and inhibition of Akt phosphorylation blocked the production of VEGF and COX-2 expression in response to LPS. Overall, this study demonstrated that engagement of TLR4 with LPS induces production of PGI2 via Akt and generates VEGF through IP receptor.
authors.affiliation: Aging-associated Vascular Disease Research Center, Department of Biochemistry & Molecular Biology, College of Medicine, Yeungnam University, Daegu 705-717, Republic of Korea.
authors.forename: Dae-Weon
authors.initials: DW
authors.lastname: Park
authors.forename: Kheewoong
authors.initials: K
authors.lastname: Baek
authors.forename: Jin-Gu
authors.initials: JG
authors.lastname: Lee
authors.forename: Yun-Ki
authors.initials: YK
authors.lastname: Park
authors.forename: Jung-Hye
authors.initials: JH
authors.lastname: Kim
authors.forename: Jae-Ryong
authors.initials: JR
authors.lastname: Kim
authors.forename: Suk-Hwan
authors.initials: SH
authors.lastname: Baek
mesh_terms: D000818:Animals; D002460:Cell Line; D011464:Epoprostenol / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*