The disintegrin and metalloproteinase ADAM10 mediates a canonical Notch-dependent regulation of IL-6 through Dll4 in human endothelial cells

• Published in: Biochemical pharmacology 2014-10, Vol.91 (4), p.510-521
• Main Authors: Pabois, Angélique, Devallière, Julie, Quillard, Thibaut, Coulon, Flora, Gérard, Nathalie, Laboisse, Christian, Toquet, Claire, Charreau, Béatrice
• Format: Article
• Language: English
• Subjects: ADAM Proteins - physiology; ADAM10; ADAM10 Protein; Amyloid Precursor Protein Secretases - physiology; Cells, Cultured; Endothelial cells; Endothelium, Vascular - cytology; Endothelium, Vascular - metabolism; Human health and pathology; Humans; Inflammation; Intercellular Signaling Peptides and Proteins - physiology; Interleukin-6 - physiology; Life Sciences; Membrane Proteins - physiology; Notch pathway; Real-Time Polymerase Chain Reaction; Receptors, Notch - physiology
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2014.08.007

ADAM10 mediates IL-6 production by endothelial cells through the activation of Dll4/Notch signaling but induces the release of IL-8, MCP-1 and soluble VCAM-1 independently of the Notch pathway. 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.