title: Increased NLRP3-dependent interleukin 1β secretion in patients with familial Mediterranean fever: correlation with MEFV genotype.
abstract: OBJECTIVE
  To define in patients affected by familial Mediterranean fever (FMF) whether or not interleukin (IL)-1β secretion (1) is enhanced, (2) correlates with the type of MEFV mutation and (3) is mediated by NLRP3.
  
  
  METHODS
  Freshly isolated monocytes from 21 patients with FMF (12 homozygous and 9 heterozygous), 14 MEFV healthy carriers and 30 healthy donors (HDs), unstimulated or after lipopolysaccharide (LPS)-induced activation, were analysed for redox state (production of reactive oxygen species (ROS) and antioxidant responses) and IL-1β and IL-1 receptor antagonist (IL-1Ra) secretion. NLRP3 down-modulation was induced by in vitro silencing of the NLRP3 gene.
  
  
  RESULTS
  LPS-stimulated monocytes from patients with FMF displayed enhanced IL-1β secretion, which correlated with number and penetrance of MEFV mutations. Silencing of NLRP3 consistently inhibited IL-1β secretion. As in other autoinflammatory diseases, FMF monocytes produced more ROS than genetically negative cells from HDs. Unlike in cryopyrin-associated periodic fever syndromes (CAPS), however, they were characterised by a conserved and sustained antioxidant response. Consistent with this finding, activated MEFV-mutated monocytes did not exhibit the functional indicators of oxidative stress observed in CAPS, including accelerated IL-1β secretion and deficient production of IL-1Ra.
  
  
  CONCLUSIONS
  MEFV-mutated monocytes display enhanced IL-1β secretion, which correlates with number of high-penetrance mutations and level of endogenous ROS. Unlike NLRP3-mutated cells, monocytes carrying MEFV mutations withstand oxidative stress and preserve IL-1Ra production, thereby limiting inflammation. Finally, in contrast with that found in the animal model, the increased secretion of IL-1β by LPS-stimulated FMF monocytes is NLRP3-dependent.
authors.affiliation: Pediatrics II Unit, G Gaslini IRCCS and University of Genoa, , Genoa, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Omenetti
authors.forename: Sonia
authors.initials: S
authors.lastname: Carta
authors.forename: Laura
authors.initials: L
authors.lastname: Delfino
authors.forename: Alberto
authors.initials: A
authors.lastname: Martini
authors.forename: Marco
authors.initials: M
authors.lastname: Gattorno
authors.forename: Anna
authors.initials: A
authors.lastname: Rubartelli
mesh_terms: D000975:Antioxidants / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D016022:Case-Control Studies; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics*; D010505:Familial Mediterranean Fever / Q000235:genetics* / Q000276:immunology*; D005260:Female; D020868:Gene Silencing; D005838:Genotype; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D009000:Monocytes / Q000276:immunology; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics / Q000276:immunology; D010375:Pedigree; D000071198:Pyrin; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C000604192:MEFV protein, human; C000604193:Mefv protein, mouse; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D000071198:Pyrin; D017382:Reactive Oxygen Species