Antagonistic effects of IL-17 and D-resolvins on endothelial Del-1 expression through a GSK-3β-CEBPβ pathway

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Tomoki Maekawa - , University of Pennsylvania, Niigata University (Autor:in)
  • Kavita Hosur - , University of Pennsylvania (Autor:in)
  • Toshiharu Abe - , University of Pennsylvania (Autor:in)
  • Alpdogan Kantarci - , Harvard University (Autor:in)
  • Athanasios Ziogas - , Technische Universität Dresden (Autor:in)
  • Baomei Wang - , University of Pennsylvania (Autor:in)
  • Thomas E. Van Dyke - , Harvard University (Autor:in)
  • Triantafyllos Chavakis - , Institut für Klinische Chemie und Laboratoriumsmedizin (Gemeinsame:r Letztautor:in)
  • George Hajishengallis - , University of Pennsylvania (Gemeinsame:r Letztautor:in)

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.

Details

OriginalspracheEnglisch
Aufsatznummer8272
FachzeitschriftNature Communications
Jahrgang6
PublikationsstatusVeröffentlicht - 16 Sept. 2015
Peer-Review-StatusJa

Externe IDs

researchoutputwizard legacy.publication#66760
Scopus 84942053330
PubMed 26374165