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PI3K/Akt signaling pathway controls PGE2‐induced ICAM‐1 expression through activation of NF‐kB

Prostaglandin E2(PGE2) is known to be the principal pro‐inflammatory prostanoid and play important roles 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. In the present study, we investigated whether EP receptor‐mediated elevation of cAMP is necessary for the effect of PGE2 on ICAM‐1 expression in bEnd.3 cerebrovascular cells. PGE2 as well as dbcAMP and forskolin stimulated ICAM‐1 expression, and induced PI3K‐dependent Akt phosphorylation. LY294002, a PI3K inhibitor, attenuated PGE2‐induced ICAM‐1 expression indicating possible involvement of PI3K in PGE2‐induced ICAM‐1 expression. This inference was further supported by the separate experiment using constitutively active and dominant negative Akt constructs. NF‐κB inhibitors such as BAY‐11 and MG‐132 diminished the PGE2‐induced ICAM‐1 expression implicating the role of NF‐κB. This result was further supported by increases in the IκB phosphorylation, translocation of NF‐κB into nucleus and the activity of NF‐κB‐responsive promoter construct. Interestingly, ectopic expression of dominant negative Akt resulted in the reduction of PGE2‐induced IκB phosphorylation. Taken together, these results suggest that PGE2‐induced ICAM‐1 expression is mediated by PI3K‐dependent NF‐κB activation.