title: The Q705K polymorphism in NLRP3 is a gain-of-function alteration leading to excessive interleukin-1β and IL-18 production.
abstract: BACKGROUND
  The Q705K polymorphism in NLRP3 has been implicated in several chronic inflammatory diseases. In this study we determine the functional role of this commonly occurring polymorphism using an in-vitro system.
  
  
  RESULTS
  NLRP3-WT and NLRP3-Q705K were retrovirally transduced into the human monocytic cell line THP-1, followed by the assessment of IL-1β and IL-18 levels in the cell culture supernatant. THP-1 cells expressing the above NLRP3 variants were sorted based upon Green Fluorescent Protein (GFP) expression. Cytokine response to alum (one of the most widely used adjuvants in vaccines) in the cells stably expressing NLRP3-WT and NLRP3-Q705K were determined. IL-1β and IL-18 levels were found to be elevated in THP-1 cells transduced with NLRP3-Q705K compared to the NLRP3-WT. Upon exposure to alum, THP-1 cells stably expressing NLRP3-Q705K displayed an increased release of IL-1β, IL-18 and TNF-α, in a caspase-1 and IL-1 receptor-dependent manner.
  
  
  CONCLUSIONS
  Collectively, these findings show that the Q705K polymorphism in NLRP3 is a gain-of-function alteration leading to an overactive NLRP3 inflammasome. The option of IL-1β blockade may be considered in patients with chronic inflammatory disorders that are unresponsive to conventional treatments.
authors.affiliation: Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden. deepti.verma@liu.se
authors.forename: Deepti
authors.initials: D
authors.lastname: Verma
authors.forename: Eva
authors.initials: E
authors.lastname: Särndahl
authors.forename: Henrik
authors.initials: H
authors.lastname: Andersson
authors.forename: Per
authors.initials: P
authors.lastname: Eriksson
authors.forename: Mats
authors.initials: M
authors.lastname: Fredrikson
authors.forename: Jan-Ingvar
authors.initials: JI
authors.lastname: Jönsson
authors.forename: Maria
authors.initials: M
authors.lastname: Lerm
authors.forename: Peter
authors.initials: P
authors.lastname: Söderkvist
mesh_terms: D019943:Amino Acid Substitution; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D058847:Inflammasomes; D020382:Interleukin-18 / Q000096:biosynthesis*; D053583:Interleukin-1beta / Q000096:biosynthesis*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D020641:Polymorphism, Single Nucleotide; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D017472:Receptors, Interleukin-1; D020170:Caspase 1