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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-Jung; Baek, Kyunghwa; Baek, Jeong-Hwa; Kim, Hyung-Ryong
- DGIST Authors
- Kim, Hyung-Ryong
- Issue Date
- International Journal of Molecular Sciences, 18(3)
- Article Type
- 6 Isopropoxy 9 Oxoxanthene 2 Carboxylic Acid; 7 [5 (4 Biphenylylmethoxy) 2 Morpholino 3 Oxocyclopentyl] 4 Heptenoic Acid; Animal; Animals; Biphenyl Compounds; Biphenyl Derivative; Bone Resorption; Calcineurin; Calcineurin; Cell Line; Cell Line; CREB; Cyclic AMP Response Element Binding Protein; Cyclic AMP Responsive Element Binding Protein; Cyclooxygenase 2; Cyclooxygenase 2; Dinoprostone; DNA Responsive Element; Drug Effects; Gene Expression; Gene Expression Regulation; Gene Expression Regulation; Genetics; High Extracellular Calcium; Metabolism; Mice; Mouse; Necrosis Factor Alpha; NF Kappa B; NFATC Transcription Factors; NFATc1; Osteoclast Differentiation Factor; Osteoclastogenesis In Vitro; PGE2; PGE2; Promoter Region; Promoter Regions, Genetic; Prostaglandin E2; Prostanoid Receptors; Protein Binding; Protein Binding; RANK Ligand; RANKL; Receptor Activator; Response Elements; Rheumatoid Arthritis; Signal Transduction; Signal Transduction; Synovial Fibroblasts; TNF Alpha; TNF Alpha; Transcription Factor NFAT; Tumor Necrosis Factor; Tumor Necrosis Factor Alpha; Xanthone Derivative; Xanthones
- 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.
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