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

Tomoki Maekawa, Kavita Hosur, Toshiharu Abe, Alpdogan Kantarci, Athanasios Ziogas, Baomei Wang, Thomas E. Van Dyke, Triantafyllos Chavakis and George Hajishengallis ()
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Tomoki Maekawa: Penn Dental Medicine, University of Pennsylvania
Kavita Hosur: Penn Dental Medicine, University of Pennsylvania
Toshiharu Abe: Penn Dental Medicine, University of Pennsylvania
Alpdogan Kantarci: Center for Periodontology, The Forsyth Institute
Athanasios Ziogas: Technische Universität Dresden
Baomei Wang: Penn Dental Medicine, University of Pennsylvania
Thomas E. Van Dyke: Center for Periodontology, The Forsyth Institute
Triantafyllos Chavakis: Technische Universität Dresden
George Hajishengallis: Penn Dental Medicine, University of Pennsylvania

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms9272

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