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- Title
Notch-1 mediates endothelial cell activation and invasion in psoriasis.
- Authors
Rooney, Peadar; Connolly, Mary; Gao, Wei; McCormick, Jennifer; Biniecka, Monika; Sullivan, Owen; Kirby, Brian; Sweeney, Cheryl; Molloy, Eamonn; Markham, Trevor; Fearon, Ursula; Veale, Douglas J.
- 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 si RNA 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 si RNA ( P < 0.05). Notch receptor-ligand interactions mediate vascular dysfunction in psoriasis and may represent a potential therapeutic target.
- Subjects
CELL proliferation; PSORIASIS &; genetics; ENDOTHELIAL cells; ACUTE phase proteins; NEOVASCULARIZATION; VASCULAR endothelial growth factors
- Publication
Experimental Dermatology, 2014, Vol 23, Issue 2, p113
- ISSN
0906-6705
- Publication type
Article
- DOI
10.1111/exd.12306