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

Abstract

NF-κB transcription factors regulate inflammatory responses to cytokines such as IL-1β and TNF-α. We tested whether PGE2 regulated nuclear localization of individual NF-κB subunits, p65 and p50, in synovial fibroblasts harvested from patients with rheumatoid arthritis (RA). IL-1β/TNF-α stimulated the translocation of p65 and p50 from the cytosol to the nucleus of human RA synovial fibroblasts, as well as NF-κB activation measured by luciferase reporter assay. PGE2 (10 nM, 6 h) enhanced p50, but inhibited p65 translocation and NF-κB 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-κB DNA binding sites. PGE2 also blocked IL-1β/TNF-α-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 IκBα in an ERK-independent manner, suggesting that PGE2 inhibits NF-κB 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-κB family dimers.

Prostaglandin E Receptor Type 4-associated Protein Interacts Directly with NF-κB1 and Attenuates Macrophage Activation

“…Consistent with our observations, PGE 2 /EP4-mediated inhibition of stimulus-induced MEK activation occurs in other cell types (45)(46)(47). We furnish here novel evidence supporting the involvement of EP4-EPRAP signaling in the suppression of MEK activation through inhibiting inducible p105 phosphorylation and degradation.…”

“…Although the effect of PGE 2 or EP4 signaling on NF-B activation probably varies by cell type (51), previous studies demonstrated that PGE 2 and EP4 signaling suppressed NF-B DNA binding activities in various inflammatory cells (46,52,53).…”

Protein isoprenylation regulates secretion of matrix metalloproteinase 1 from rheumatoid synovial fibroblasts: Effects of statins and farnesyl and geranylgeranyl transferase inhibitors

“…tained from patients at the time of total joint arthroplasty, as previously described (44). The collection and use of human RASFs and OASFs were reviewed and approved by the Institutional Board of Research Associates, New York University School of Medicine (New York, NY).…”

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

“…Paradoxically, PGE 2 has also been demonstrated to have antiinflammatory roles in various animal models [10,11]. The dichotomous role of PGE 2 in inflammation is underscored by in vitro findings showing that its effects on cytokine/chemokine release can be pro-inflammatory [12,13] or anti-inflammatory [14][15][16], depending on the system. Similar to PGE 2 , the cytokine IFN-c has also been shown to have dual, apparently contradictory, roles in inflammation (as recently reviewed in ref.…”