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

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

Research output: Contribution to journalArticle

Abstract

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-1β-mediated process. Brief treatment with IL-1β upregulated endothelial VCAM1 and Notch ligand Jagged1. IL-1β decreased Notch1 mRNA levels, but levels of the active Notch1ICD protein remained constant. IL-1β-mediated VCAM1 induction was downregulated in endothelial cells subjected to pretreatment with a pharmacological inhibitor of the γ-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 naïve endothelial cells upregulated VCAM1 per se and amplified IL-1β-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-1β. Thus, IL-1β regulates Notch1 and Notch4 activity in opposite directions, consistent with a selective targeting of Notch1 in inflamed endothelium.

Original languageEnglish
Pages (from-to)43216-43229
Number of pages14
JournalOncotarget
Volume6
Issue number41
DOIs
Publication statusPublished - 2015

Keywords

  • Endothelial cells
  • IL-1β
  • Notch1
  • Notch4
  • Pathology Section
  • VCAM1

ASJC Scopus subject areas

  • Oncology

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    Verginelli, F., Adesso, L., Limon, I., Alisi, A., Gueguen, M., Panera, N., Giorda, E., Raimondi, L., Ciarapica, R., Campese, A. F., Screpanti, I., Stifani, S., Kitajewski, J., Miele, L., Rota, R., & Locatelli, F. (2015). Activation of an endothelial Notch1-Jagged1 circuit induces VCAM1 expression, an effect amplified by interleukin-1β. Oncotarget, 6(41), 43216-43229. https://doi.org/10.18632/oncotarget.6456