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Int. J. Mol. Sci. 2017, 18(3), 495; doi:10.3390/ijms18030495

TNFα Increases RANKL Expression via PGE2-Induced Activation of NFATc1

1
Department of Molecular Genetics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 08826, Korea
2
Department of Pharmacology, College of Dentistry and Research Institute of Oral Science, Gangneung-Wonju National University, Gangwon-do 25457, Korea
3
Graduate School, DGIST, Daegu 42988, Korea
*
Authors to whom correspondence should be addressed.
Academic Editor: Masatoshi Maki
Received: 23 December 2016 / Revised: 12 February 2017 / Accepted: 20 February 2017 / Published: 24 February 2017
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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Abstract

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
Keywords: TNFα; RANKL; PGE2; NFATc1; CREB TNFα; RANKL; PGE2; NFATc1; CREB
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MDPI and ACS Style

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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