Downstream activation of NF-κB in the EDA-A1/EDAR signalling in Sjögren's syndrome and its regulation by the ubiquitin-editing enzyme A20

Autor:	Margherita Sisto, Sabrina Lisi, Dario Domenico Lofrumento, Amilcare Barca
Přispěvatelé:	Sisto, M, Barca, Amilcare, Lofrumento, Dario Domenico, Lisi, S.
Rok vydání:	2016
Předmět:	0301 basic medicine TNFAIP3 Salivary Glands NF-κB Pathogenesis chemistry.chemical_compound NF-KappaB Inhibitor alpha Ubiquitin immune system diseases Immunology and Allergy RNA Small Interfering Nuclear Protein education.field_of_study biology Edar Receptor Intracellular Signaling Peptides and Proteins NF-kappa B Nuclear Proteins Ectodysplasins DNA-Binding Proteins A20 Sjogren's Syndrome I-kappa B Proteins Sjögren's syndrome RNA Interference Human Signal Transduction Ectodysplasin DNA-Binding Protein Immunology Population Salivary Gland 03 medical and health sciences medicine Humans Gene silencing Ectodysplasin A receptor education Tumor Necrosis Factor alpha-Induced Protein 3 Autoimmune disease Epithelial Cell business.industry Epithelial Cells Original Articles EDAR medicine.disease 030104 developmental biology chemistry Intracellular Signaling Peptides and Protein EDA-A1 biology.protein I-kappa B Protein business
Zdroj:	Clinical and Experimental Immunology. 184:183-196
ISSN:	1365-2249 0009-9104
DOI:	10.1111/cei.12764
Popis:	Summary Sjögren's syndrome (SS) is an autoimmune disease and the second most common chronic systemic rheumatic disorder. Prevalence of primary SS in the general population has been estimated to be approximately 1–3%, whereas secondary SS has been observed in 10–20% of patients with rheumatoid arthritis, systemic lupus erythematosus (SLE) and scleroderma. Despite this, its exact aetiology and pathogenesis are largely unexplored. Nuclear factor-kappa B (NF-κB) signalling mechanisms provide central controls in SS, but how these pathways intersect the pathological features of this disease is unclear. The ubiquitin-editing enzyme A20 (tumour necrosis factor-α-induced protein 3, TNFAIP3) serves as a critical inhibitor on NF-κB signalling. In humans, polymorphisms in the A20 gene or a deregulated expression of A20 are often associated with several inflammatory disorders, including SS. Because A20 controls the ectodysplasin-A1 (EDA-A1)/ectodysplasin receptor (EDAR) signalling negatively, and the deletion of A20 results in excessive EDA1-induced NF-κB signalling, this work investigates the expression levels of EDA-A1 and EDAR in SS human salivary glands epithelial cells (SGEC) and evaluates the hypothesis that SS SGEC-specific deregulation of A20 results in excessive EDA1-induced NF-κB signalling in SS. Our approach, which combines the use of siRNA-mediated gene silencing and quantitative pathway analysis, was used to elucidate the role of the A20 target gene in intracellular EDA-A1/EDAR/NF-κB pathway in SS SGEC, holding significant promise for compound selection in drug discovery.
Databáze:	OpenAIRE
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