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

  • Nat Commun. 2015 Sep 16:6:8272. doi: 10.1038/ncomms9272.
Tomoki Maekawa  1  2 ,  Kavita Hosur  1 ,  Toshiharu Abe  1 ,  Alpdogan Kantarci  3 ,  Athanasios Ziogas  4 ,  Baomei Wang  1 ,  Thomas E Van Dyke  3 ,  Triantafyllos Chavakis  4 ,  George Hajishengallis  1
Affiliations
  • 1. Department of Microbiology, Penn Dental Medicine, University of Pennsylvania, 240 S. 40th Street, Philadelphia, Pennsylvania 19104, USA.
  • 2. 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.
  • 3. Department of Applied Oral Sciences, Center for Periodontology, The Forsyth Institute, 245 First Street, Cambridge, Massachusetts 02142, USA.
  • 4. Department of Clinical Pathobiochemistry and Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Fetscherstraße 74, Dresden 01307, Germany.
PMID: 26374165 DOI: 10.1038/ncomms9272
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.