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

Author

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  • Tomoki Maekawa

    (Penn Dental Medicine, University of Pennsylvania
    Niigata University, Graduate School of Medical and Dental Sciences, Research Center for Advanced Oral Science)

  • 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)

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.

Suggested Citation

  • Tomoki Maekawa & Kavita Hosur & Toshiharu Abe & Alpdogan Kantarci & Athanasios Ziogas & Baomei Wang & Thomas E. Van Dyke & Triantafyllos Chavakis & George Hajishengallis, 2015. "Antagonistic effects of IL-17 and D-resolvins on endothelial Del-1 expression through a GSK-3β-C/EBPβ pathway," Nature Communications, Nature, vol. 6(1), pages 1-12, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9272
    DOI: 10.1038/ncomms9272
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