title: The disintegrin and metalloproteinase ADAM10 mediates a canonical Notch-dependent regulation of IL-6 through Dll4 in human endothelial cells.
abstract: Although the involvement of the disintegrin and metalloproteinase ADAM10 in several areas of vascular biology is now clearly established, its role in vascular inflammation and in Notch signaling at the endothelial level remains unclear. In this study, we demonstrated that ADAM10 specifically localizes in the CD31(+) endothelial cells (ECs) in normal human cardiac tissues and in cultured primary arterial ECs. In vitro, ADAM10 drives a specific regulation of the Notch pathway in vascular ECs. Using an ADAM10 gain and loss of function approach we show an ADAM10-dependent regulation of Dll1 and Dll4 expression in association with changes in Hes1 and Hey1 expression. We also identified IL-6, IL-8, MCP-1 and sVCAM-1 as novel targets of ADAM10 upon inflammation. Although Notch pathway does not seem to be required for the production of IL-8, MCP-1 and sVCAM-1, the release of IL-6 by ECs occurred through ADAM10 and a canonical Notch signaling pathway, dependent of γ-secretase activity. Moreover, sustained expression of Dll4 mediated by ADAM10 elicits an increased release of IL-6 suggesting a strong implication of the specific Dll4 signaling in this mechanism. Modulation of IL-6 mediated by ADAM10/Notch signaling required PI3K activity. Thus, our findings suggest that ADAM10/Dll4 signaling is a major signaling pathway in ECs driving inflammatory events involved in inflammation and immune cell recruitment.
authors.affiliation: INSERM UMR1064, Centre de Recherche en Transplantation et Immunologie, LabEx IGO and LabEx Transplantex, Nantes F44000, France; CHU de Nantes, Institut de Transplantation-Urologie-Néphrologie, ITUN, Nantes F44000, France; LUNAM, Université de Nantes, Faculté de Médecine, Nantes F44000, France.
authors.forename: Angélique
authors.initials: A
authors.lastname: Pabois
authors.affiliation: INSERM UMR1064, Centre de Recherche en Transplantation et Immunologie, LabEx IGO and LabEx Transplantex, Nantes F44000, France; CHU de Nantes, Institut de Transplantation-Urologie-Néphrologie, ITUN, Nantes F44000, France; LUNAM, Université de Nantes, Faculté de Médecine, Nantes F44000, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Devallière
authors.affiliation: INSERM UMR1064, Centre de Recherche en Transplantation et Immunologie, LabEx IGO and LabEx Transplantex, Nantes F44000, France; CHU de Nantes, Institut de Transplantation-Urologie-Néphrologie, ITUN, Nantes F44000, France; LUNAM, Université de Nantes, Faculté de Médecine, Nantes F44000, France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Quillard
authors.affiliation: INSERM UMR1064, Centre de Recherche en Transplantation et Immunologie, LabEx IGO and LabEx Transplantex, Nantes F44000, France; CHU de Nantes, Institut de Transplantation-Urologie-Néphrologie, ITUN, Nantes F44000, France; LUNAM, Université de Nantes, Faculté de Médecine, Nantes F44000, France.
authors.forename: Flora
authors.initials: F
authors.lastname: Coulon
authors.affiliation: INSERM UMR1064, Centre de Recherche en Transplantation et Immunologie, LabEx IGO and LabEx Transplantex, Nantes F44000, France; CHU de Nantes, Institut de Transplantation-Urologie-Néphrologie, ITUN, Nantes F44000, France; LUNAM, Université de Nantes, Faculté de Médecine, Nantes F44000, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Gérard
authors.affiliation: LUNAM, Université de Nantes, Faculté de Médecine, Nantes F44000, France; Service d'Anatomie Pathologique, CHU de Nantes, Nantes F44000, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Laboisse
authors.affiliation: LUNAM, Université de Nantes, Faculté de Médecine, Nantes F44000, France; Service d'Anatomie Pathologique, CHU de Nantes, Nantes F44000, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Toquet
authors.affiliation: INSERM UMR1064, Centre de Recherche en Transplantation et Immunologie, LabEx IGO and LabEx Transplantex, Nantes F44000, France; CHU de Nantes, Institut de Transplantation-Urologie-Néphrologie, ITUN, Nantes F44000, France; LUNAM, Université de Nantes, Faculté de Médecine, Nantes F44000, France. Electronic address: Beatrice.Charreau@univ-nantes.fr.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Charreau
mesh_terms: D051722:ADAM Proteins / Q000502:physiology*; D000072197:ADAM10 Protein; D048868:Adaptor Proteins, Signal Transducing; D053829:Amyloid Precursor Protein Secretases / Q000502:physiology*; D002135:Calcium-Binding Proteins; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D015850:Interleukin-6 / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D051880:Receptors, Notch / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D008565:Membrane Proteins; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human
keywords: ADAM10; Endothelial cells; Inflammation; Notch pathway