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TNF alpha Increases RANKL Expression via PGE(2)-Induced Activation of NFATc1

TNF alpha Increases RANKL Expression via PGE(2)-Induced Activation of NFATc1
Park, Hyun-JungBaek, KyunghwaBaek, Jeong-HwaKim, Hyung-Ryong
DGIST Authors
Kim, Hyung-Ryong
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Gene Expression Regulation6 Isopropoxy 9 Oxoxanthene 2 Carboxylic Acid7 [5 (4 Biphenylylmethoxy) 2 Morpholino 3 Oxocyclopentyl] 4 Heptenoic AcidAnimalAnimalsBiphenyl CompoundsBiphenyl DerivativeBone ResorptionCalcineurinCalcineurinCell LineCell LineCREBCyclic AMP Response Element Binding ProteinCyclic AMP Responsive Element Binding ProteinCyclooxygenase 2Cyclooxygenase 2DinoprostoneDNA Responsive ElementDrug EffectsGene ExpressionHigh Extracellular CalciumMetabolismMiceMouseNecrosis Factor AlphaNF Kappa BGene Expression RegulationGeneticsNFATC Transcription FactorsNFATc1Osteoclast Differentiation FactorOsteoclastogenesis In VitroXanthonesPGE2PGE2Promoter RegionPromoter Regions, GeneticProstaglandin E2Prostanoid ReceptorsProtein BindingProtein BindingRANK LigandRANKLReceptor ActivatorResponse ElementsRheumatoid ArthritisSignal TransductionSignal TransductionSynovial FibroblastsTNF AlphaTNF AlphaTranscription Factor NFATTumor Necrosis FactorTumor Necrosis Factor AlphaXanthone Derivative
Tumor necrosis factor α (TNFα) is known to upregulate the expression of receptor activator of NF-κB ligand (RANKL). We investigated the role of the calcineurin/nuclear factor of activated T-cells (NFAT) signaling pathway in TNFα-induced RANKL expression in C2C12 and primary cultured mouse calvarial cells. TNFα-induced RANKL expression was blocked by the calcineurin/NFAT pathway inhibitors. TNFα increased NFAT transcriptional activity and subsequent RANKL promoter binding. Mutations in the NFAT-binding element (MT(N)) suppressed TNFα-induced RANKL promoter activity. TNFα increased prostaglandin E2 (PGE2) production, which in turn enhanced NFAT transcriptional activity and binding to the RANKL promoter. MT(N) suppressed PGE2-induced RANKL promoter activity. TNFα and PGE2 increased the expression of RANKL, NFAT cytoplasmic-1 (NFATc1), cAMP response element-binding protein (CREB), and cyclooxygenase 2 (COX2); which increment was suppressed by indomethacin, a COX inhibitor. Mutations in the CRE-like element blocked PGE2-induced RANKL promoter activity. PGE2 induced the binding of CREB to the RANKL promoter, whereas TNFα increased the binding of both CREB and NFATc1 to this promoter through a process blocked by indomethacin. The PGE2 receptor antagonists AH6809 and AH23848 blocked TNFα-induced expression of RANKL, NFATc1, and CREB; transcriptional activity of NFAT; and binding of NFATc1 or CREB to the RANKL promoter. These results suggest that TNFα-induced RANKL expression depends on PGE2 production and subsequent transcriptional activation/enhanced binding of NFATc1 and CREB to the RANKL promoter. © 2017 by the authors. Licensee MDPI, Basel, Switzerland.
Multidisciplinary Digital Publishing Institute (MDPI)
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