Prostaglandin E2 (PGE2) is known to be the principal pro-inflammatory prostanoid and play an important role in brain disease through binding to four G protein-coupled receptor (EP1-4). However, there have been contradictory reports on its actions in inflammation processes. For instance, PGE2 inhibits or stimulates ICAM-1 expression depending on the cell type and experimental conditions. Furthermore, the effect of PGE2 on ICAM-1 expression in cerebrovascular endothelial cells is mostly unknown. In this study, it was investigated the roles of PGE2 in the expression of ICAM-1 in primary cultured mouse brain endothelial cells and bEnd.3 cells and therein involved signaling pathways. PGE2 induced ICAM-1 expression at the levels of protein and mRNA levels in the time and dose dependent manner and the effects was mediated by EP1/4. In order to delineate the intracellular signaling pathway, cAMP dependent signaling events were investigated. Though dbcAMP and forskolin mimicked the effect of PGE2, PKA inhibitors did not show significant effect on PGE2-induced ICAM-1 expression. However, involvement of Epac was confirmed by experiments using specific stimulators and inhibitors, and siRNA technology. PGE2 and dbcAMP stimulated phosphorylation of Akt and GSK-3β, suggesting the role of PI3K/Akt in PGE2-induced ICAM-1 expression. This inference was supported by the separate experiment using a PI3K inhibitor, LY294002, constitutive active (CA) and dominant negative (DN) Akt constructs. PGE2 induced the activation of NF-κB, critical regulator of ICAM-1 expression and NF-κB inhibitors blocked PGE2 and dbcAMP-induced ICAM-1 expression. Interestingly, loss of Akt activity results in inhibition of NF-κB activation. Taken together, these data suggest that PGE2 induces ICAM-1 expression through activation of EP4/cAMP/Epac and PI3K/NF-κB axis.