Manipulation of distinct NFκB proteins alters interleukin-1β-induced human rheumatoid synovial fibroblast prostaglandin E2 formation

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Abstract

Interleukin 1β (IL-1β) up-regulates human rheumatoid synovial fibroblast (RSF) 85-kDa phospholipase A2 (PLA2) and mitogen-inducible cyclooxygenase (COX) II. Promoter regions for these genes contain a motif that closely resembles the 'classic' NFκB consensus site. Immunoblot analysis identified NFκB1 (p50), RelA (p65), and c-Rel in RSF. Upon IL-1β- stimulation, p65 and c-Rel but not p50 protein levels were reduced suggesting nuclear translocation. IL-1β-induced RSF nuclear extracts contained a p65- containing complex, which bound to the classical NFκB consensus motif. An NFκB classical oligonucleotide decoy produced a concentration-dependent decrease in IL-1-stimulated PGE2 production (IC50 = 2 μM), indicating a role of NFκB. Utilization of antisense technology showed that p65 but not p50 or c-Rel mediated IL-1β-stimulated PGE2 formation. Treated RSF could not transcribe COX II or 85-kDa PLA2 mRNA, which reduced their respective proteins. Interestingly, stimulated IL-8 production was not inhibited by the classical NFκB decoy but was reduced by treatment with antisense to both p65 and c-Rel supporting preferential binding of c-Rel-p65 to the 'alternative' IL-8 κB motif. Taken together, these data provide the first direct evidence for a role of p65 in COX II and 85-kDa PLA2 gene induction and support the IL-1 activation and participation of distinct NFκB protein dimers in RSF prostanoid and IL-8 formation.

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Roshak, A. K., Jackson, J. R., McGough, K., Chabot-Fletcher, M., Mochan, E., & Marshall, L. A. (1996). Manipulation of distinct NFκB proteins alters interleukin-1β-induced human rheumatoid synovial fibroblast prostaglandin E2 formation. Journal of Biological Chemistry, 271(49), 31496–31501. https://doi.org/10.1074/jbc.271.49.31496

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