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Nat Commun. 2015 Sep 16;6:8272. doi: 10.1038/ncomms9272.

Antagonistic effects of IL-17 and D-resolvins on endothelial Del-1 expression through a GSK-3β-C/EBPβ pathway.

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Department of Microbiology, Penn Dental Medicine, University of Pennsylvania, 240 S. 40th Street, Philadelphia, Pennsylvania 19104, USA.
Niigata University, Graduate School of Medical and Dental Sciences, Research Center for Advanced Oral Science, 2-5274 Gakkocho-dori, Chuo-ku, Niigata 951-8514, Japan.
Department of Applied Oral Sciences, Center for Periodontology, The Forsyth Institute, 245 First Street, Cambridge, Massachusetts 02142, USA.
Department of Clinical Pathobiochemistry and Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Fetscherstraße 74, Dresden 01307, Germany.


Del-1 is an endothelial cell-secreted anti-inflammatory protein. In humans and mice, Del-1 expression is inversely related to that of IL-17, which inhibits Del-1 through hitherto unidentified mechanism(s). Here we show that IL-17 downregulates human endothelial cell expression of Del-1 by targeting a critical transcription factor, C/EBPβ. Specifically, IL-17 causes GSK-3β-dependent phosphorylation of C/EBPβ, which is associated with diminished C/EBPβ binding to the Del-1 promoter and suppressed Del-1 expression. This inhibitory action of IL-17 can be reversed at the GSK-3β level by PI3K/Akt signalling induced by D-resolvins. The biological relevance of this regulatory network is confirmed in a mouse model of inflammatory periodontitis. Intriguingly, resolvin-D1 (RvD1) confers protection against IL-17-driven periodontal bone loss in a Del-1-dependent manner, indicating an RvD1-Del-1 axis against IL-17-induced pathological inflammation. The dissection of signalling pathways regulating Del-1 expression provides potential targets to treat inflammatory diseases associated with diminished Del-1 expression, such as periodontitis and multiple sclerosis.

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