期刊
NATURE COMMUNICATIONS
卷 6, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms9272
关键词
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资金
- NIH [DE015254, DE021685, DE024716, AI068730, DE020906, DE015566, DE019938]
- Deutsche Forschungsgemeinschaft [CH279/5-1, CH279/6-2, SFB-TR 127]
- German Federal Government
- European Research Council (ENDHOMRET)
- German State Government
- Grants-in-Aid for Scientific Research [15H06229] Funding Source: KAKEN
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/EBP beta. Specifically, IL-17 causes GSK-3 beta-dependent phosphorylation of C/EBP beta, which is associated with diminished C/EBP beta binding to the Del-1 promoter and suppressed Del-1 expression. This inhibitory action of IL-17 can be reversed at the GSK-3 beta 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.
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