Prostaglandin E2 Suppresses Chemokine Production in Human Macrophages through the EP4 Receptor

Pro-inflammatory pathways participate in the pathogenesis of atherosclerosis. However, the role of endogenous anti-inflammatory pathways in atheroma has received much less attention. Therefore, using cDNA microarrays, we screened for genes regulated by prostaglandin E 2 (PGE 2 ), a potential endogenous anti-inflammatory mediator, in lipopolysaccharide (LPS)-treated human macrophages (MΦ). PGE 2 (50 n m ) attenuated LPS-induced mRNA and protein expression of chemokines including monocyte chemoattractant protein-1, interleukin-8, macrophage inflammatory protein-1α and -1β, and interferon-inducible protein-10. PGE 2 also inhibited the tumor necrosis factor-α-, interferon-γ-, and interleukin-1β-mediated expression of these chemokines. In contrast to the case of MΦ, PGE 2 did not suppress chemokine expression in human endothelial and smooth muscle cells (SMC) treated with LPS and pro-inflammatory cytokines. To assess the potential paracrine effect of endogenous PGE 2 on macrophage-derived chemokine production, we co-cultured MΦ with SMC in the presence of LPS. In these co-cultures, cyclooxygenase-2-dependent PGE 2 production exceeded that in the mono-cultures, and MIP-1β declined significantly compared with MΦ cultured without SMC. We further documented prominent expression of the PGE 2 receptor EP4 in MΦ in both culture and human atheroma. Moreover, a selective EP4 antagonist completely reversed PGE 2 -mediated suppression of chemokine production. Thus, endogenous PGE 2 may modulate inflammation during atherogenesis and other inflammatory diseases by suppressing macrophage-derived chemokine production via the EP4 receptor.