Oncotarget

Research Papers: Pathology:

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 and Franco Locatelli _

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Oncotarget. 2015; 6:43216-43229. https://doi.org/10.18632/oncotarget.6456

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Abstract

Federica Verginelli1, Laura Adesso1, Isabelle Limon2, Anna Alisi3, Marie Gueguen2, Nadia Panera3, Ezio Giorda4, Lavinia Raimondi1, Roberta Ciarapica1, Antonio F. Campese5, Isabella Screpanti5, Stefano Stifani6, Jan Kitajewski7, Lucio Miele8, Rossella Rota1,* and Franco Locatelli1,9,*

1 Department of Oncohematology, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy

2 Department of Sorbonne Universités, UPMC University Paris 06, CNRS, UMR, IBPS, Paris, France

3 Liver Research Unit, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy

4 Department of Unit of Flow Cytometry, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy

5 Department of Molecular Medicine, Sapienza University, Rome, Italy

6 Center for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, QC, Canada

7 Departments of Pathology and Ob/Gyn, Columbia University Medical Center, New York, NY, USA

8 Department of Genetics and Stanley Scott Cancer Center, Louisiana State University Health Sciences Center and Louisiana Cancer Research Consortium, New Orleans, LA, USA

9 Dipartimento di Scienze Pediatriche, Università di Pavia, Pavia PV, Italy

* These authors have contributed equally to this work

Correspondence to:

Franco Locatelli, email:

Rossella Rota, email:

Keywords: Notch1, Notch4, endothelial cells, IL-1β, VCAM1, Pathology Section

Received: June 11, 2015 Accepted: November 21, 2015 Published: December 03, 2015

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.


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