biostudies-literatureMaekawa TNIDCR NIH HHSEuropean Research CouncilNIAID NIH HHS8272https://www.ebi.ac.uk/biostudies/studies/S-EPMC4573473biostudies-literatureUnknown6Del-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.Nature communicationsAntagonistic effects of IL-17 and D-resolvins on endothelial Del-1 expression through a GSK-3β-C/EBPβ pathway.PMC4573473AI068730P01 AI068730R01 DE019938R21 DE020906DE015254DE020906R01 DE021685DE015566DE024716DE019938R01 DE015566281296DE021685R01 DE024716R01 DE015254Chavakis TZiogas AHosur KMaekawa TKantarci AWang BHajishengallis GAbe TVan Dyke TEfalseAntagonistic effects of IL-17 and D-resolvins on endothelial Del-1 expression through a GSK-3β-C/EBPβ pathway.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.2015-01-01T00:00:00Z2015 Sep2024-11-20T18:52:32.513Z2019-03-27T01:58:34ZS-EPMC45734732637416510.1038/ncomms9272