PGE2 differentially regulates monocyte-derived dendritic cell cytokine responses depending on receptor usage (EP2/EP4)

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Abstract

Dendritic cells (DCs) are central players in coordinating immune responses, both innate and adaptive. While the role of lipid mediators in the immune response has been the subject of many investigations, the precise role of prostaglandins has often been plagued by contradictory studies. In this study, we examined the role of PGE2 on human DC function. Although studies have suggested that PGE2 specifically plays a role in DC motility and cytokine release profile, the precise receptor usage and signaling pathways involved remain unclear. In this report we found that irrespective of the human donor, monocyte-derived dendritic cells (MoDCs) express three of the four PGE2 receptor subtypes (EP2–4), although only EP2 and EP4 were active with respect to cytokine production. Using selective EP receptor antagonists and agonists, we demonstrate that PGE2 coordinates control of IL-23 release (a promoter of Th17, an autoimmune associated T cell subset) in a dose-dependent manner by differential use of EP2 and EP4 receptors in LPS-activated MoDCs. This is in contrast to IL-12, which is dose dependently inhibited by PGE2 through both receptor subtypes. Low concentrations (∼1–10 nM) of PGE2 promoted IL-23 production via EP4 receptors, while at higher (>50 nM), but still physiologically relevant concentrations, IL-23 is suppressed by an EP2 dependent mechanism. These results can be explained by differential regulation of the common subunit, IL-12p40, and IL-23p19, by EP2 and EP4. By these means, PGE2 can act as a regulatory switch of immune responses depending on its concentration in the microenvironment. In addition, we believe these results may also explain why seemingly conflicting biological functions assigned to PGE2 have been reported in the literature, as the concentration of ligand (PGE2) fundamentally alters the nature of the response. This finding also highlights the potential of designing therapeutics which differentially target these receptors.

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