title: Differential cytokine secretion results from p65 and c-Rel NF-κB subunit signaling in peripheral blood mononuclear cells of TNF receptor-associated periodic syndrome patients.
abstract: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory condition caused by mutations in the TNFRSF1A gene which encodes the tumor necrosis factor (TNF) receptor, TNFR1. We investigated the effect of three high penetrance and three low penetrance TNFRSF1A mutations upon NF-κB transcription factor family subunit activity, and the resulting impact upon secretion of 25 different cytokines. Whilst certain mutations resulted in elevated NF-κB p65 subunit activity, others instead resulted in elevated c-Rel subunit activity. Interestingly, high p65 activity was associated with elevated IL-8 secretion, whereas high c-Rel activity increased IL-1β and IL-12 secretion. In conclusion, while all six TNFRSF1A mutations showed enhanced NF-κB activity, different mutations stimulated distinct NF-κB family subunit activities, and this in turn resulted in the generation of unique cytokine secretory profiles.
authors.affiliation: Centre for Diabetes, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Whitechapel, London E1 2AT, UK.
authors.forename: Belinda
authors.initials: B
authors.lastname: Nedjai
authors.forename: Graham A
authors.initials: GA
authors.lastname: Hitman
authors.forename: Leigh D
authors.initials: LD
authors.lastname: Church
authors.forename: Kirsten
authors.initials: K
authors.lastname: Minden
authors.forename: Margo L
authors.initials: ML
authors.lastname: Whiteford
authors.forename: Shane
authors.initials: S
authors.lastname: McKee
authors.forename: Susanna
authors.initials: S
authors.lastname: Stjernberg
authors.forename: Tom
authors.initials: T
authors.lastname: Pettersson
authors.forename: Annamari
authors.initials: A
authors.lastname: Ranki
authors.forename: Philip N
authors.initials: PN
authors.lastname: Hawkins
authors.forename: Peter D
authors.initials: PD
authors.lastname: Arkwright
authors.forename: Michael F
authors.initials: MF
authors.lastname: McDermott
authors.forename: Mark D
authors.initials: MD
authors.lastname: Turner
mesh_terms: D000328:Adult; D002648:Child; D016207:Cytokines / Q000276:immunology*; D005260:Female; D005334:Fever; D056660:Hereditary Autoinflammatory Diseases / Q000097:blood / Q000235:genetics / Q000276:immunology; D006801:Humans; D007118:Immunoassay; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020569:Proto-Oncogene Proteins c-rel / Q000097:blood / Q000276:immunology*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000097:blood / Q000276:immunology*; D055815:Young Adult
chemical_list: D016207:Cytokines; D020569:Proto-Oncogene Proteins c-rel; D047888:Receptors, Tumor Necrosis Factor, Type I; C506235:TNFRSF1A protein, human; D051996:Transcription Factor RelA