Resolution of inflammation:: Prostaglandin E2 dissociates nuclear trafficking of individual NF-κB Subunits (p65, p50) in stimulated rheumatoid synovial fibroblasts

NF-kappa B transcription factors regulate inflammatory responses to cytokines such as IL-1 beta and TNF-alpha. We tested whether PGE(2) regulated nuclear localization of individual NF-kappa B subunits, p65 and p50, in synovial fibroblasts harvested from patients with rheumatoid arthritis (RA). IL-1 beta/TNF-alpha stimulated the translocation of p65 and p50 from the cytosol to the nucleus of human RA synovial fibroblasts, as well as NF-kappa B activation measured by luciferase reporter assay. PGE(2) (10 nM, 6 h) enhanced p50, but inhibited p65 translocation and NF-kappa B activation. In contrast, depletion of endogenous PGE(2) by ibuprofen (100 mu M) and celecoxib (5 mu M) enhanced p65, but inhibited p50 nuclear translocation as well as binding to NF-kappa B DNA binding sites. PGE(2) also blocked IL-1 beta/TNF-alpha-stimulated ERK activation, and the ERK inhibitor, PD98059, mimicked PGE(2) in blocking p65, but enhancing p50 nuclear translocation, suggesting that the effects of PGE(2) on p65 and p50 are mediated via effects on ERK. PGE(2) also enhanced the expression of I kappa B alpha in an ERK-independent manner, suggesting that PGE(2) inhibits NF-kappa B activation by both ERK-dependent and -independent mechanisms. Our data indicate that PGE(2) may act to attenuate cytokine-induced inflammatory responses in RA synovial fibroblasts via regulation of the localization of specific NF-kappa B family dimers.