title: Activation of an endothelial Notch1-Jagged1 circuit induces VCAM1 expression, an effect amplified by interleukin-1β.
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.
authors.affiliation: Department of Oncohematology, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Verginelli
authors.affiliation: Department of Oncohematology, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Adesso
authors.affiliation: Department of Sorbonne Universités, UPMC University Paris 06, CNRS, UMR, IBPS, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Limon
authors.affiliation: Liver Research Unit, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Alisi
authors.affiliation: Department of Sorbonne Universités, UPMC University Paris 06, CNRS, UMR, IBPS, Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Gueguen
authors.affiliation: Liver Research Unit, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Panera
authors.affiliation: Department of Unit of Flow Cytometry, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
authors.forename: Ezio
authors.initials: E
authors.lastname: Giorda
authors.affiliation: Department of Oncohematology, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
authors.forename: Lavinia
authors.initials: L
authors.lastname: Raimondi
authors.affiliation: Department of Oncohematology, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Ciarapica
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: Antonio F
authors.initials: AF
authors.lastname: Campese
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Screpanti
authors.affiliation: Center for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
authors.forename: Stefano
authors.initials: S
authors.lastname: Stifani
authors.affiliation: Departments of Pathology and Ob/Gyn, Columbia University Medical Center, New York, NY, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Kitajewski
authors.affiliation: Department of Genetics and Stanley Scott Cancer Center, Louisiana State University Health Sciences Center and Louisiana Cancer Research Consortium, New Orleans, LA, USA.
authors.forename: Lucio
authors.initials: L
authors.lastname: Miele
authors.affiliation: Department of Oncohematology, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Rota
authors.affiliation: Department of Oncohematology, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.|Dipartimento di Scienze Pediatriche, Università di Pavia, Pavia PV, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002460:Cell Line; D002469:Cell Separation; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000502:physiology; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering; D051381:Rats; D051881:Receptor, Notch1 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis*
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D053583:Interleukin-1beta; C000606273:JAG1 protein, human; C000606275:Jag1 protein, rat; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins; D019010:Vascular Cell Adhesion Molecule-1
keywords: IL-1β; Notch1; Notch4; Pathology Section; VCAM1; endothelial cells