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

J Biol Chem

Leducq Center for Cardiovascular Research, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

Published: November 2002

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Article 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 E(2) (PGE(2)), a potential endogenous anti-inflammatory mediator, in lipopolysaccharide (LPS)-treated human macrophages (MPhi). PGE(2) (50 nm) attenuated LPS-induced mRNA and protein expression of chemokines including monocyte chemoattractant protein-1, interleukin-8, macrophage inflammatory protein-1alpha and -1beta, and interferon-inducible protein-10. PGE(2) also inhibited the tumor necrosis factor-alpha-, interferon-gamma-, and interleukin-1beta-mediated expression of these chemokines. In contrast to the case of MPhi, 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 MPhi 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-1beta declined significantly compared with MPhi cultured without SMC. We further documented prominent expression of the PGE(2) receptor EP4 in MPhi 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.

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http://dx.doi.org/10.1074/jbc.M204810200DOI Listing

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