title: Inhibition of the NF-κB pathway as a candidate therapeutic strategy for cryopyrin-associated periodic syndrome.
abstract: OBJECTIVE
  Cryopyrin-associated periodic syndrome (CAPS) is caused by unrestricted IL-1β release due to mutation of the gene coding NLRP3. This study aimed to clarify whether NLRP3-related IL-1β release is dependent on the NF-κB pathway.
  
  
  METHODS
  Peripheral blood mononuclear cells (PBMCs) from healthy subjects or patients with Muckle-Wells syndrome were primed with LPS and subsequently stimulated by ATP. Human umbilical vein endothelial cells (HUVECs) were cultured with the supernatant obtained from LPS-plus ATP-stimulated PBMCs. Expression of proinflammatory molecules was estimated using RT-PCR, ELISA or immunochemical staining, in the presence or absence of an NF-κB inhibitor (-)-dehydroxymethylepoxyquinomicin (DHMEQ).
  
  
  RESULTS
  DHMEQ inhibited expression of proIL-1β and NLRP3 by normal PBMCs primed with LPS, resulting in inhibition of caspase-1 activation and IL-1β secretion by the cells after subsequent stimulation with ATP. DHMEQ also inhibited expression of IL-1β, TNFα, IL-6 and VCAM-1 by HUVECs. Patient cells released IL-1β spontaneously or by ATP-stimulation even without LPS-priming. Both the spontaneous and stimulated IL-1β releases were inhibited by DHMEQ without affecting viability of the cells.
  
  
  CONCLUSIONS
  These results clearly indicate that IL-1β production through the NLRP3 inflammasome is dependent on the NF-κB pathway, which could be a good target for the development of a novel therapeutic strategy for CAPS.
authors.affiliation: Department of Microbiology and Immunology, Tokyo Medical and Dental University Graduate School of Health Care Sciences , Tokyo , Japan.
authors.forename: Satoka
authors.initials: S
authors.lastname: Shimogaki
authors.forename: Sayaka
authors.initials: S
authors.lastname: Ito
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Komatsu
authors.forename: Ryuji
authors.initials: R
authors.lastname: Koike
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Miyasaka
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Kubota
mesh_terms: D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D056587:Cryopyrin-Associated Periodic Syndromes / Q000188:drug therapy* / Q000378:metabolism; D003512:Cyclohexanones / Q000494:pharmacology* / Q000627:therapeutic use; D016207:Cytokines / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
chemical_list: D001549:Benzamides; D003512:Cyclohexanones; D016207:Cytokines; D016328:NF-kappa B; C464444:dehydroxymethylepoxyquinomicin