title: Antagonistic effects of IL-17 and D-resolvins on endothelial Del-1 expression through a GSK-3β-C/EBPβ pathway.
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.
authors.affiliation: Department of Microbiology, Penn Dental Medicine, University of Pennsylvania, 240 S. 40th Street, Philadelphia, Pennsylvania 19104, USA.|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.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Maekawa
authors.affiliation: Department of Microbiology, Penn Dental Medicine, University of Pennsylvania, 240 S. 40th Street, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Kavita
authors.initials: K
authors.lastname: Hosur
authors.affiliation: Department of Microbiology, Penn Dental Medicine, University of Pennsylvania, 240 S. 40th Street, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Abe
authors.affiliation: Department of Applied Oral Sciences, Center for Periodontology, The Forsyth Institute, 245 First Street, Cambridge, Massachusetts 02142, USA.
authors.forename: Alpdogan
authors.initials: A
authors.lastname: Kantarci
authors.affiliation: Department of Clinical Pathobiochemistry and Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Fetscherstraße 74, Dresden 01307, Germany.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Ziogas
authors.affiliation: Department of Microbiology, Penn Dental Medicine, University of Pennsylvania, 240 S. 40th Street, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Baomei
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Applied Oral Sciences, Center for Periodontology, The Forsyth Institute, 245 First Street, Cambridge, Massachusetts 02142, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Van Dyke
authors.affiliation: Department of Clinical Pathobiochemistry and Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Fetscherstraße 74, Dresden 01307, Germany.
authors.forename: Triantafyllos
authors.initials: T
authors.lastname: Chavakis
authors.affiliation: Department of Microbiology, Penn Dental Medicine, University of Pennsylvania, 240 S. 40th Street, Philadelphia, Pennsylvania 19104, USA.
authors.forename: George
authors.identifier: http://orcid.org/0000-0001-7392-8852
authors.initials: G
authors.lastname: Hajishengallis
mesh_terms: D016301:Alveolar Bone Loss / Q000235:genetics / Q000276:immunology*; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000276:immunology* / Q000378:metabolism; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015815:Cell Adhesion Molecules; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005881:Gingiva / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects / Q000276:immunology*; D000071679:Glycogen Synthase Kinase 3 beta; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D036341:Intercellular Signaling Peptides and Proteins; D020381:Interleukin-17 / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D010518:Periodontitis / Q000235:genetics / Q000276:immunology*; D009195:Peroxidase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D004281:Docosahexaenoic Acids; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D036341:Intercellular Signaling Peptides and Proteins; D020381:Interleukin-17; D009195:Peroxidase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C545012:CEBPB protein, human; C545013:Cebpb protein, mouse; C110183:EDIL3 protein, human; C491706:Edil3 protein, mouse; C518399:resolvin D1; C545423:resolvin D2; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse