resolvin-d1 and Periodontitis

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.

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