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

Abstract

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 EM 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-λ-activation pathway, including IFN-λ itself. This effect of the PGE2/EP4 axis on IFN-λ is a reciprocal phenomenon since IFN-λ blocks PGE2 release and blocks EP receptor expression. The mutually antagonistic relationship between IFN-λ and PGE2 extends to downstream cytokine and chemokine release; PGE2 counters the effects of IFN-λ, on the release of IP-10, IL-8, TNF-α and IL-1β. To gain further insight into IFN-λ-mediated cellular events in RA, we assessed the effects of IFN-λ on gene expression in FLS. We observed an IFN-λ-depeodent 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-λ, which may represent a fundamental mechanism of immune control in diseases such as RA. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.