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)12 formation in macrophages. The LPS-stimulated COX-2 expression and PGI(2) 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 PGI(2)) 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 PGI(2) via Akt and generates VEGF through IP receptor. (C) 2007 Elsevier Inc. All rights reserved.