title: Pattern of interleukin-1beta secretion in response to lipopolysaccharide and ATP before and after interleukin-1 blockade in patients with CIAS1 mutations.
abstract: OBJECTIVE
  To examine the synthesis, processing, and secretion of interleukin-1beta (IL-1beta), as well as the clinical and biologic effects of IL-1 blockade, in patients with chronic infantile neurologic, cutaneous, articular (CINCA) syndrome and Muckle-Wells syndrome (MWS), in an effort to understand the molecular mechanisms linking mutations of the CIAS1 gene and IL-1beta hypersecretion, and the underlying response to IL-1 receptor antagonist (IL-1Ra).
  
  
  METHODS
  Six patients with CINCA syndrome or MWS were treated with IL-1Ra and followed up longitudinally. Monocytes obtained from the patients and from 24 healthy donors were activated with lipopolysaccharide (LPS) for 3 hours, and intracellular and secreted IL-1beta levels were determined by Western blotting and enzyme-linked immunosorbent assay before and after exposure to exogenous ATP.
  
  
  RESULTS
  LPS-induced IL-1beta secretion was markedly increased in monocytes from patients with CIAS1 mutations. However, unlike in healthy subjects, secretion of IL-1beta was not induced by exogenous ATP. Treatment with IL-1Ra resulted in a dramatic clinical improvement, which was paralleled by an early and strong down-regulation of LPS-induced IL-1beta secretion by the patients' cells in vitro.
  
  
  CONCLUSIONS
  Our results showed that the requirements of ATP stimulation for IL-1beta release observed in healthy individuals are bypassed in patients bearing CIAS1 mutations. This indicates that cryopyrin is the direct target of ATP and that the mutations release the protein from the requirement of ATP for activation. In addition, the dramatic amelioration induced by IL-1Ra treatment is at least partly due to the strong decrease in IL-1beta secretion that follows the first injections of the antagonist. These findings may have implications for other chronic inflammatory conditions characterized by increased IL-1beta.
authors.affiliation: Second Division of Pediatrics, IRCCS, Istituto G. Gaslini, Genoa, Italy. marcogattorno@ospedale-gaslini.ge.it
authors.forename: Marco
authors.initials: M
authors.lastname: Gattorno
authors.forename: Sara
authors.initials: S
authors.lastname: Tassi
authors.forename: Sonia
authors.initials: S
authors.lastname: Carta
authors.forename: Laura
authors.initials: L
authors.lastname: Delfino
authors.forename: Francesca
authors.initials: F
authors.lastname: Ferlito
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Pelagatti
authors.forename: Andrea
authors.initials: A
authors.lastname: D'Osualdo
authors.forename: Antonella
authors.initials: A
authors.lastname: Buoncompagni
authors.forename: Maria Giannina
authors.initials: MG
authors.lastname: Alpigiani
authors.forename: Maria
authors.initials: M
authors.lastname: Alessio
authors.forename: Alberto
authors.initials: A
authors.lastname: Martini
authors.forename: Anna
authors.initials: A
authors.lastname: Rubartelli
mesh_terms: D015746:Abdominal Pain / Q000235:genetics* / Q000276:immunology*; D000255:Adenosine Triphosphate / Q000008:administration & dosage; D000293:Adolescent; D000328:Adult; D001168:Arthritis / Q000235:genetics* / Q000276:immunology*; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D005260:Female; D005334:Fever / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors*; D053583:Interleukin-1beta / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008137:Longitudinal Studies; D008297:Male; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009422:Nervous System Diseases / Q000235:genetics* / Q000276:immunology*; D013577:Syndrome; D014581:Urticaria / Q000235:genetics* / Q000276:immunology*
chemical_list: D002352:Carrier Proteins; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D000255:Adenosine Triphosphate