Mutual antagonistic relationship between prostaglandin E2 and IFN‐γ: Implications for rheumatoid arthritis

Prostaglandin E2 (PGE2) is a major mediator of inflammation and is present at high concentrations in the synovial fluid of rheumatoid arthritis (RA) patients. PGE2, acting through the EP4 receptor, has both pro- and anti-inflammatory roles in vivo. To shed light on this dual role of PGE2, we investigated its effects in whole blood and in primary human fibroblast-like synoviocytes (FLS). Gene expression analysis in human leukocytes, confirmed at the protein level, revealed an EP4-dependent inhibition of the expression of genes involved in the IFN-γ-activation pathway, including IFN-γ itself. This effect of the PGE2/EP4 axis on IFN-γ is a reciprocal phenomenon since IFN-γ blocks PGE2 release and blocks EP receptor expression. The mutually antagonistic relationship between IFN-γ and PGE2 extends to downstream cytokine and chemokine release; PGE2 counters the effects of IFN-γ, on the release of IP-10, IL-8, TNF-α and IL-1β. To gain further insight into IFN-γ-mediated cellular events in RA, we assessed the effects of IFN-γ on gene expression in FLS. We observed an IFN-γ-dependent up-regulation of macrophage-attracting chemokines, and down-regulation of metalloprotease expression. These results suggest the existence of a mutually antagonistic relationship between PGE2 and IFN-γ, which may represent a fundamental mechanism of immune control in diseases such as RA. Supporting Information for this article is available at www.wiley-vch.de/contents/jc_2040/2008/38170_s.pdf