| First Author | Maekawa T | Year | 2015 |
| Journal | Nat Commun | Volume | 6 |
| Pages | 8272 | PubMed ID | 26374165 |
| Mgi Jnum | J:226990 | Mgi Id | MGI:5699490 |
| Doi | 10.1038/ncomms9272 | Citation | Maekawa T, et al. (2015) Antagonistic effects of IL-17 and D-resolvins on endothelial Del-1 expression through a GSK-3beta-C/EBPbeta pathway. Nat Commun 6:8272 |
| abstractText | 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/EBPbeta. Specifically, IL-17 causes GSK-3beta-dependent phosphorylation of C/EBPbeta, which is associated with diminished C/EBPbeta binding to the Del-1 promoter and suppressed Del-1 expression. This inhibitory action of IL-17 can be reversed at the GSK-3beta 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. |
