Prostaglandin E2 suppresses chemokine production in human macrophages through the EP4 receptor

Abstract

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 E2 (PGE2), a potential endogenous anti-inflammatory mediator, in lipopolysaccharide (LPS)treated human macrophages (MΦ). PGE2 (50 nM) attenuated LPS-induced mRNA and protein expression of chemokines including monocyte chemoattractant protein-1, interleukin-8, macrophage inflammatory protein-1α and -β, and interferon-inducible protein-10. PGE2 also inhibited the tumor necrosis factor-α-, interferon-y-, and interleukin-1β-mediated expression of these chemokines. In contrast to the case of MΦ, PGE2 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 PGE2 on macrophagederived chemokine production, we co-cultured MΦ with SMC in the presence of LPS. In these co-cultures, cyclooxygenase-2-dependent PGE2 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 PGE2 receptor EP4 in MΦ in both culture and human atheroma. Moreover, a selective EP4 antagonist completely reversed PGE2-mediated suppression of chemokine production. Thus, endogenous PGE2 may modulate inflammation during atherogenesis and other inflammatory diseases by suppressing macrophage-derived chemokine production via the EP4 receptor.