Resolution of inflammation: prostaglandin E2 dissociates nuclear trafficking of individual NF-kappaB subunits (p65, p50) in stimulated rheumatoid synovial fibroblasts.
NF-kappaB transcription factors regulate inflammatory responses to cytokines such as IL-1beta and TNF-alpha. We tested whether PGE2 regulated nuclear localization of individual NF-kappaB subunits, p65 and p50, in synovial fibroblasts harvested from patients with rheumatoid arthritis (RA). IL-1beta/TNF-alpha stimulated the translocation of p65 and p50 from the cytosol to the nucleus of human RA synovial fibroblasts, as well as NF-kappaB activation measured by luciferase reporter assay. PGE2 (10 nM, 6 h) enhanced p50, but inhibited p65 translocation and NF-kappaB activation. In contrast, depletion of endogenous PGE2 by ibuprofen (100 microM) and celecoxib (5 microM) enhanced p65, but inhibited p50 nuclear translocation as well as binding to NF-kappaB DNA binding sites. PGE2 also blocked IL-1beta/TNF-alpha-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 IkappaBalpha in an ERK-independent manner, suggesting that PGE2 inhibits NF-kappaB 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-kappaB family dimers.
Gomez
Paul F
PF
Department of Rheumatology, Hospital for Joint Diseases and Department of Medicine, New York University School of Medicine, New York, NY 10003, USA.
Pillinger
Michael H
MH
Attur
Mukundan
M
Marjanovic
Nada
N
Dave
Mander
M
Park
Jean
J
Bingham
Clifton O
CO
Al-Mussawir
Hayf
H
Abramson
Steven B
SB
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008954:Models, Biological; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D007375:Interleukin-1; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D011994:Recombinant Proteins; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D015232:Dinoprostone