PGE2 stimulates COX-2 expression via EP2/4 receptors and acts in synergy with IL-1β in human follicular dendritic cell-like cells

Abstract

PGE2 is the major lipid mediator of inflammation produced by multiple cell types including follicular dendritic cells (FDCs) of the lymphoid tissue. We have investigated the immunoregulatory function of PGE2 and its production mechanism using FDC-like cells isolated from human tonsil. Our recent observation of COX-2-inducing effect of PGE2 prompted us to identify the responsible receptor in this study. Pharmacologic approaches were adopted and Western blotting was utilized to measure protein expression levels. Agonists selective for EP2 and EP4 significantly stimulated COX-2 expression, while antagonists for these receptors prevented PGE2 from triggering COX-2 induction. The combined addition of EP2 and EP4 antagonists resulted in further inhibition of PGE2. In contrast, EP1 and EP3 antagonists failed to exhibit the inhibitory effect on PGE2-induced COX-2 expression. Since PGE2 achieves COX-2 induction by repressing Akt activation in FDC-like cells, we confirmed EP2 and EP4 being the targets of PGE2 by examining the effects of E-prostanoid (EP) agonists and antagonists on the level of Akt phosphorylation. After the identification of PGE2 receptor, we examined the effect of PGE2 on IL-1β-induced COX-2 expression. PGE2 and IL-1β brought about a synergistic induction of COX-2 expression. Taken together, this study implies the impact of the combined role of eicosanoids and cytokines in inflammatory milieu.