A Novel Signaling Pathway Mediates the Inhibition of CCL3/4 Expression by Prostaglandin E2

In response to pathogen-associated molecular patterns, dendritic cells initiate an innate immune response characterized by expression and release of proinflammatory cytokines and chemokines. The extent of the inflammatory response is limited by various endogenous factors, including lipid mediators such as prostaglandin E(2) (PGE(2)). We described previously the inhibitory effect of PGE(2) on the expression and release of the inflammatory chemokines CCL3 and CCL4 from activated dendritic cells. In this study we describe a novel PGE(2) signaling pathway that proceeds through EP-2 --> cAMP --> EPAC --> phosphatidylinositol 3-kinase --> protein kinase B --> GSK-3 and results in increased DNA binding of the CCAAT displacement protein (CDP), a potent mammalian transcriptional repressor. The direct link between CDP and CCL3/4 transcription was established in knock-down experiments using CDP small interference RNA.