title: Tumor necrosis factor receptor I from patients with tumor necrosis factor receptor-associated periodic syndrome interacts with wild-type tumor necrosis factor receptor I and induces ligand-independent NF-kappaB activation.
abstract: OBJECTIVE
  To investigate the molecular consequences of expressing mutated forms of tumor necrosis factor receptor I (TNFRI) as found in patients with TNFR-associated periodic syndrome (TRAPS).
  
  
  METHODS
  We cloned and expressed full-length wild-type (WT) and T50K and P46L variants of TNFRI using a new tightly regulated doxycycline-dependent expression system. This system enabled the study of molecular interactions between these receptors at both physiologic and pathophysiologic levels of expression.
  
  
  RESULTS
  We used chemical crosslinking on the cell surface to show that WT and mutant forms of TNFRI, derived from TRAPS patients, interact in the absence of TNF ligand. Doxycycline-controlled up-regulation of one TNFRI allele, either WT or mutant, caused down-regulation of the other allele, indicating dynamic control of cell surface assembly. We also demonstrated that increased expression of mutant TNFRI (T50K) was associated with a parallel increase in NF-kappaB p65 (RelA) subunit activation, which did not occur with increased expression of WT TNFRI.
  
  
  CONCLUSIONS
  The T50K TRAPS-related variant is capable of sustaining inappropriate NF-kappaB activation, resulting in persistent auto-inflammation in target organs such as skin, synovial membrane, and the central nervous system. We conclude that some of the inflammatory processes seen in TRAPS do not involve direct interaction of TNF with its receptors, but that other proinflammatory mechanisms capable of up-regulating TNFRI expression may cause cellular activation through the NF-kappaB signaling pathway.
authors.affiliation: Barts and The London Queen Mary's School of Medicine and Dentistry, University of London, London, UK.
authors.forename: Nasim
authors.initials: N
authors.lastname: Yousaf
authors.forename: David J
authors.initials: DJ
authors.lastname: Gould
authors.forename: Ebun
authors.initials: E
authors.lastname: Aganna
authors.forename: Linda
authors.initials: L
authors.lastname: Hammond
authors.forename: Rita M
authors.initials: RM
authors.lastname: Mirakian
authors.forename: Mark D
authors.initials: MD
authors.lastname: Turner
authors.forename: Graham A
authors.initials: GA
authors.lastname: Hitman
authors.forename: Michael F
authors.initials: MF
authors.lastname: McDermott
authors.forename: Yuti
authors.initials: Y
authors.lastname: Chernajovsky
mesh_terms: D003001:Cloning, Molecular; D010505:Familial Mediterranean Fever / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D008024:Ligands; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D047990:TNF Receptor-Associated Factor 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D008024:Ligands; D016328:NF-kappa B; D047990:TNF Receptor-Associated Factor 1