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Article Dans Une Revue Oncotarget Année : 2015

Activation of an endothelial Notch1-Jagged1 circuit induces VCAM1 expression, an effect amplified by interleukin-1 beta

Federica Verginelli
  • Fonction : Auteur
Laura Adesso
  • Fonction : Auteur
Anna Alisi
  • Fonction : Auteur
Marie Gueguen
  • Fonction : Auteur
Nadia Panera
  • Fonction : Auteur
Ezio Giorda
  • Fonction : Auteur
Lavinia Raimondi
  • Fonction : Auteur
Roberta Ciarapica
  • Fonction : Auteur
Antonio F. Campese
  • Fonction : Auteur
Isabella Screpanti
  • Fonction : Auteur
Stefano Stifani
  • Fonction : Auteur
Jan Kitajewski
  • Fonction : Auteur
Lucio Miele
  • Fonction : Auteur
Rossella Rota
Franco Locatelli
  • Fonction : Auteur

Résumé

The Notch1 and Notch4 signaling pathways regulate endothelial cell homeostasis. Inflammatory cytokines induce the expression of endothelial adhesion molecules, including VCAM1, partly by downregulating Notch4 signaling. We investigated the role of endothelial Notch1 in this IL-1 beta-mediated process. Brief treatment with IL-1 beta upregulated endothelial VCAM1 and Notch ligand Jagged1. IL-1 beta decreased Notch1 mRNA levels, but levels of the active Notch1ICD protein remained constant. IL-1 beta-mediated VCAM1 induction was downregulated in endothelial cells subjected to pretreatment with a pharmacological inhibitor of the.-secretase, which activates Notch receptors, producing NotchICD. It was also downregulated in cells in which Notch1 and/or Jagged1 were silenced. Conversely, the forced expression of Notch1ICD in naive endothelial cells upregulated VCAM1 per se and amplified IL-1 beta-mediated VCAM1 induction. Jagged1 levels increased and Notch4 signaling was downregulated in parallel. Finally, Notch1ICD and Jagged1 expression was upregulated in the endothelium of the liver in a model of chronic liver inflammation. In conclusion, we describe here a cell-autonomous, pro-inflammatory endothelial Notch1-Jagged1 circuit (i) triggering the expression of VCAM1 even in the absence of inflammatory cytokines and (ii) enhancing the effects of IL-1 beta. Thus, IL-1 beta regulates Notch1 and Notch4 activity in opposite directions, consistent with a selective targeting of Notch1 in inflamed endothelium.

Dates et versions

hal-01545428 , version 1 (22-06-2017)

Identifiants

Citer

Federica Verginelli, Laura Adesso, Isabelle Limon, Anna Alisi, Marie Gueguen, et al.. Activation of an endothelial Notch1-Jagged1 circuit induces VCAM1 expression, an effect amplified by interleukin-1 beta. Oncotarget, 2015, 6 (41), pp.43216-43229. ⟨10.18632/oncotarget.6456⟩. ⟨hal-01545428⟩
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