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Resolution of Inflammation: Prostaglandin E₂ Dissociates Nuclear Trafficking of Individual NF-B Subunits (p65, p50) in Stimulated Rheumatoid Synovial Fibroblasts¹

Paul F. Gomez^2,*, Michael H. Pillinger^2,3,*,, Mukundan Attur^*, Nada Marjanovic^*, Mander Dave^*, Jean Park^*, Clifton O. Bingham, III^*, Hayf Al-Mussawir^* and Steven B. Abramson^*

^* Department of Rheumatology, Hospital for Joint Diseases and Department of Medicine, New York University School of Medicine, New York, NY 10003; and Department of Medicine, New York Harbor Veterans Affairs Healthcare System New York Campus, New York, NY 10010

NF-B transcription factors regulate inflammatory responses to cytokines such as IL-1 and TNF-. We tested whether PGE₂ regulated nuclear localization of individual NF-B subunits, p65 and p50, in synovial fibroblasts harvested from patients with rheumatoid arthritis (RA). IL-1/TNF- stimulated the translocation of p65 and p50 from the cytosol to the nucleus of human RA synovial fibroblasts, as well as NF-B activation measured by luciferase reporter assay. PGE₂ (10 nM, 6 h) enhanced p50, but inhibited p65 translocation and NF-B activation. In contrast, depletion of endogenous PGE₂ by ibuprofen (100 µM) and celecoxib (5 µM) enhanced p65, but inhibited p50 nuclear translocation as well as binding to NF-B DNA binding sites. PGE₂ also blocked IL-1/TNF--stimulated ERK activation, and the ERK inhibitor, PD98059, mimicked PGE₂ in blocking p65, but enhancing p50 nuclear translocation, suggesting that the effects of PGE₂ on p65 and p50 are mediated via effects on ERK. PGE₂ also enhanced the expression of IB in an ERK-independent manner, suggesting that PGE₂ inhibits NF-B activation by both ERK-dependent and -independent mechanisms. Our data indicate that PGE₂ may act to attenuate cytokine-induced inflammatory responses in RA synovial fibroblasts via regulation of the localization of specific NF-B family dimers.

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