title: Downstream activation of NF-κB in the EDA-A1/EDAR signalling in Sjögren's syndrome and its regulation by the ubiquitin-editing enzyme A20.
abstract: 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.
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University of Bari Medical School, Bari, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Sisto
authors.affiliation: Neuropathology Unit, Institute of Experimental Neurology and Division of Neuroscience, IRCCS San Raffaele Scientific Institute (Section of Lecce), Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Barca
authors.affiliation: Department of Biological and Environmental Sciences and Technologies, Section of Human Anatomy, University of Salento, Lecce, Italy.
authors.forename: D D
authors.initials: DD
authors.lastname: Lofrumento
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University of Bari Medical School, Bari, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Lisi
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D053331:Ectodysplasins / Q000378:metabolism*; D053339:Edar Receptor / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D012469:Salivary Glands / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction; D012859:Sjogren's Syndrome / Q000473:pathology*; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D004268:DNA-Binding Proteins; C506008:EDAR protein, human; D053331:Ectodysplasins; D053339:Edar Receptor; D020672:I-kappa B Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D000072000:NF-KappaB Inhibitor alpha; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
keywords: A20; EDA-A1; EDAR; NF-κB; Sjögren's syndrome