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TNFα Increases RANKL Expression via PGE2-Induced Activation of NFATc1

Department of Molecular Genetics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 08826, Korea
Department of Pharmacology, College of Dentistry and Research Institute of Oral Science, Gangneung-Wonju National University, Gangwon-do 25457, Korea
Graduate School, DGIST, Daegu 42988, Korea
Authors to whom correspondence should be addressed.
Academic Editor: Masatoshi Maki
Int. J. Mol. Sci. 2017, 18(3), 495;
Received: 23 December 2016 / Revised: 12 February 2017 / Accepted: 20 February 2017 / Published: 24 February 2017
(This article belongs to the Section Biochemistry)
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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. View Full-Text

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Park, H.-J.; Baek, K.; Baek, J.-H.; Kim, H.-R. TNFα Increases RANKL Expression via PGE2-Induced Activation of NFATc1. Int. J. Mol. Sci. 2017, 18, 495.

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