E-prostanoid (EP)2/EP4 receptor-dependent maturation of human monocyte-derived dendritic cells and induction of helper T2 polarization

Prostaglandin (PG) E-2 induces dendritic cell maturation in cooperation with proinflammatory cytokines [such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta]. To clarify the involvement of E-prostanoid (EP) receptors in the effect of prostaglandin E-2 on human monocyte-derived dendritic cell (MoDC) maturation, we examined the effect of four types of EP receptor-selective agonists on MoDC maturation. PGE(2) as well as 11,15-O-dimethyl prostaglandin (E2ONO-AE1-259-01) (EP2 receptor agonist) and ONO-AE1-329 (EP4 receptor agonist) concentration dependently enhanced the expression of CD80, CD86, CD83, and HLA-DR on MoDCs during maturation, especially in the presence of TNF-alpha, whereas 17S-2,5-ethano-6-oxo-17,20-dimethyl prostaglandin E-1 (EP1 receptor agonist) and 16S-9-deoxy-90-chloro-15-deoxy-16-hyfroxy-17,17-trimethylene-19,20-didehydro prostaglandin F-2 (EP3 receptor agonist) showed no effect. The maximal effect of ONO-AE1-259-01 was higher than that of ONO-AE1-329; however, the stimulation with ONO-AE1-259-01 was less effective than that with PGE(2). Simultaneous stimulation with both EP receptor agonists produced additive effects and 11-deoxy-PGE(1) (EP2/EP4 receptor mixed agonist) mimicked the effects of PGE(2). Dibutyryl cAMP mimicked the effects of PGE(2), indicating the mediation of PGE(2) action by cAMP. Matured MoDCs induced by PGE(2) or EP2 and/or EP4 receptor agonists showed a decrease in lipopolysaccharide (LPS)-stimulated IL-12p70, IL-6, and IL-10 production. The coculture of naive T cells with matured MoDCs induced under different conditions showed that EP2/EP4-stimulated MoDCs preferentially induced alloresponsive helper T (Th)2 cells. Together, it was concluded that the cooperative stimulation of EP2 and EP4 receptor subtypes by PGE2 promoted MoDC maturation and inhibited LPS-induced cytokine production in MoDCs. The matured MoDCs under such conditions preferably induced Th2 polarization, indicating the importance of EP2 and EP4 receptors in the determination of Th1/Th2 development of naive T cells.