Mutual antagonistic relationship between prostaglandin E(2) and IFN-gamma: Implications for rheumatoid arthritis.
Prostaglandin E(2) (PGE(2)) is a major mediator of inflammation and is present at high concentrations in the synovial fluid of rheumatoid arthritis (RA) patients. PGE(2), acting through the EP4 receptor, has both pro- and anti-inflammatory roles in vivo. To shed light on this dual role of PGE(2), 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-gamma-activation pathway, including IFN-gamma itself. This effect of the PGE(2)/EP4 axis on IFN-gamma is a reciprocal phenomenon since IFN-gamma blocks PGE(2) release and blocks EP receptor expression. The mutually antagonistic relationship between IFN-gamma and PGE(2) extends to downstream cytokine and chemokine release; PGE(2) counters the effects of IFN-gamma, on the release of IP-10, IL-8, TNF-alpha and IL-1beta. To gain further insight into IFN-gamma-mediated cellular events in RA, we assessed the effects of IFN-gamma on gene expression in FLS. We observed an IFN-gamma-dependent up-regulation of macrophage-attracting chemokines, and down-regulation of metalloprotease expression. These results suggest the existence of a mutually antagonistic relationship between PGE(2) and IFN-gamma, which may represent a fundamental mechanism of immune control in diseases such as RA.
Department of Biochemistry and Molecular Biology, Merck Frosst Center for Therapeutic Research, Kirkland, Canada.
Marie-Claude
MC
Mathieu
Simon
S
Lord-Dufour
Virginie
V
Bernier
Yves
Y
Boie
Jason D
JD
Burch
Patsy
P
Clark
Danielle
D
Denis
Yongxin
Y
Han
James R
JR
Mortimer
Alex G
AG
Therien
D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D015232:Dinoprostone / Q000097:blood / Q000378:metabolism*; D015536:Down-Regulation; D015870:Gene Expression; D053263:Gene Regulatory Networks; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D018078:Receptors, Prostaglandin E / Q000276:immunology / Q000378:metabolism*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013582:Synovial Fluid / Q000166:cytology / Q000276:immunology; D015854:Up-Regulation
D016207:Cytokines; C545650:PTGER4 protein, human; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D007371:Interferon-gamma; D015232:Dinoprostone