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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Alveolar Bone Loss / genetics
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Alveolar Bone Loss / immunology*
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Animals
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CCAAT-Enhancer-Binding Protein-beta / immunology*
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CCAAT-Enhancer-Binding Protein-beta / metabolism
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Calcium-Binding Proteins
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Carrier Proteins / genetics
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Carrier Proteins / immunology*
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Carrier Proteins / metabolism
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Cell Adhesion Molecules
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Chromatin Immunoprecipitation
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Disease Models, Animal
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Docosahexaenoic Acids / pharmacology
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Down-Regulation
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Enzyme-Linked Immunosorbent Assay
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Gingiva / metabolism
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Glycogen Synthase Kinase 3 / drug effects
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Glycogen Synthase Kinase 3 / immunology*
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Glycogen Synthase Kinase 3 beta
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Human Umbilical Vein Endothelial Cells
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Humans
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Immunoblotting
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Immunoprecipitation
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Intercellular Signaling Peptides and Proteins
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Interleukin-17 / immunology*
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Mice
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Mice, Knockout
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Periodontitis / genetics
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Periodontitis / immunology*
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Peroxidase / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation
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Proto-Oncogene Proteins c-akt / metabolism
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Real-Time Polymerase Chain Reaction
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Signal Transduction
Substances
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CCAAT-Enhancer-Binding Protein-beta
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CEBPB protein, human
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Calcium-Binding Proteins
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Carrier Proteins
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Cebpb protein, mouse
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Cell Adhesion Molecules
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EDIL3 protein, human
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Edil3 protein, mouse
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Intercellular Signaling Peptides and Proteins
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Interleukin-17
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resolvin D1
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resolvin D2
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Docosahexaenoic Acids
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Peroxidase
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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Proto-Oncogene Proteins c-akt
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Glycogen Synthase Kinase 3