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The Q705K polymorphism in NLRP3 is a gain-of-function alteration leading to excessive interleukin-1β and IL-18 production
Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.ORCID iD: 0000-0002-4319-7208
Division of Microbiology and Molecular Medicine, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
Division of Rheumatology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 4, article id e34977Article in journal (Refereed) Published
Abstract [en]

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.

Principal findings: 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.

Place, publisher, year, edition, pages
San Fransisco, USA: Public Library of Science , 2012. Vol. 7, no 4, article id e34977
National Category
Medical and Health Sciences Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:oru:diva-41296DOI: 10.1371/journal.pone.0034977ISI: 000305347400028PubMedID: 22529966Scopus ID: 2-s2.0-84859877626OAI: oai:DiVA.org:oru-41296DiVA, id: diva2:780269
Funder
Swedish Research Council, 529-2003-5994 2005-7046 2007-2673 2009-3821 K2010-64X-21463-01-3 K2010-57X-21435-01-3 K2010-55X-20451-04-03
Note

Funding Agencies:

Medical Research Council of Southeast Sweden FORSS-8984

County Council of Östergötland

King Gustaf V Memorial Foundation

Available from: 2015-01-14 Created: 2015-01-14 Last updated: 2017-12-05Bibliographically approved

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Särndahl, Eva

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