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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alveolar Bone Loss / genetics
  • Alveolar Bone Loss / immunology*
  • Animals
  • CCAAT-Enhancer-Binding Protein-beta / immunology*
  • CCAAT-Enhancer-Binding Protein-beta / metabolism
  • Calcium-Binding Proteins
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology*
  • Carrier Proteins / metabolism
  • Cell Adhesion Molecules
  • Chromatin Immunoprecipitation
  • Disease Models, Animal
  • Docosahexaenoic Acids / pharmacology
  • Down-Regulation
  • Enzyme-Linked Immunosorbent Assay
  • Gingiva / metabolism
  • Glycogen Synthase Kinase 3 / drug effects
  • Glycogen Synthase Kinase 3 / immunology*
  • Glycogen Synthase Kinase 3 beta
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-17 / immunology*
  • Mice
  • Mice, Knockout
  • Periodontitis / genetics
  • Periodontitis / immunology*
  • Peroxidase / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction

Substances

  • CCAAT-Enhancer-Binding Protein-beta
  • CEBPB protein, human
  • Calcium-Binding Proteins
  • Carrier Proteins
  • Cebpb protein, mouse
  • Cell Adhesion Molecules
  • EDIL3 protein, human
  • Edil3 protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-17
  • resolvin D1
  • resolvin D2
  • Docosahexaenoic Acids
  • Peroxidase
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3