title: Notch-1 mediates endothelial cell activation and invasion in psoriasis.
abstract: Notch receptor-ligand interactions are critical for cell proliferation, differentiation and survival; however, the role of Notch signalling in psoriasis remains to be elucidated. Serum amyloid A (A-SAA) is an acute-phase protein with cytokine-like properties, regulates cell survival pathways and is implicated in many inflammatory conditions. To examine the role of Notch-1 signalling in the pathogenesis of psoriasis, Notch-1, DLL-4, Jagged-1, Hrt-1/Hrt-2, A-SAA, Factor VIII and vascular endothelial growth factor (VEGF) mRNA and/or protein expression in psoriasis skin biopsies, serum and dHMVEC were assessed by immunohistology, dual-immunofluorescence, real-time PCR, ELISA and Western blotting. A-SAA-induced angiogenesis and invasion in the presence of Notch-1 siRNA was assessed by matrigel tube formation assays and Transwell invasion assay. Increased Notch-1, its ligand DLL-4 and Hrt-1 expression were demonstrated in lesional skin compared with non-lesional skin, with greatest expression observed in the dermal vasculature (P < 0.05). Dual-immunofluorescent staining demonstrated co-localization of Notch-1 to endothelial cell marker Factor VIII. A significant increase in A-SAA levels was demonstrated in psoriasis serum compared with healthy control serum (P < 0.05), and A-SAA expression was higher in lesional skin compared with non-lesional. In dHMVEC, A-SAA significantly induced Jagged-1, Hrt-1 and VEGF mRNA expression (P < 0.05) and activated Notch-1 IC indicative of transcriptional regulation. In contrast, A-SAA significantly inhibited DLL-4 mRNA expression (P < 0.05). Finally A-SAA-induced angiogenesis and invasion were inhibited by Notch-1 siRNA (P < 0.05). Notch receptor-ligand interactions mediate vascular dysfunction in psoriasis and may represent a potential therapeutic target.
authors: Department of Rheumatology, Dublin Academic Medical Centre and the Conway Institute of Biomolecular and Biomedical Research, UCD, Dublin 4, Ireland.
authors: Peadar
authors: P
authors: Rooney
authors: Mary
authors: M
authors: Connolly
authors: Wei
authors: W
authors: Gao
authors: Jennifer
authors: J
authors: McCormick
authors: Monika
authors: M
authors: Biniecka
authors: Owen
authors: O
authors: Sullivan
authors: Brian
authors: B
authors: Kirby
authors: Cheryl
authors: C
authors: Sweeney
authors: Eamonn
authors: E
authors: Molloy
authors: Trevor
authors: T
authors: Markham
authors: Ursula
authors: U
authors: Fearon
authors: Douglas J
authors: DJ
authors: Veale
mesh_terms: D000328:Adult; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000473:pathology*; D005169:Factor VIII / Q000032:analysis; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D055806:Microvessels / Q000473:pathology; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000473:pathology*; D011565:Psoriasis / Q000378:metabolism / Q000473:pathology*; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000494:pharmacology; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000072099:Serrate-Jagged Proteins; D000685:Serum Amyloid A Protein / Q000502:physiology; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D005169:Factor VIII; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins; D000685:Serum Amyloid A Protein; C485631:HEY1 protein, human; C000606273:JAG1 protein, human; C497761:NOTCH1 protein, human
keywords: Jagged-1; Notch-1; angiogenesis; invasion; psoriasis; serum amyloid A