title: NLRP3 mediates NF-κB activation and cytokine induction in microbially induced and sterile inflammation.
abstract: Nucleotide-binding domain and leucine-rich repeat-containing family, pyrin domain containing 3 (NLRP3) has recently emerged as a central regulator of innate immunity and inflammation in response to both sterile inflammatory and microbial invasion signals. Although its ability to drive proteolytic procaspase-1 processing has drawn more attention, NLPR3 can also activate NF-κB. To clarify the physiological relevance of this latter function, we examined the effect of NLRP3 on NF-κB activation and cytokine induction in RNA-interference-based NLRP3-knockdown cell lines generated from the human monocytic cell line THP-1. Knocking down NLRP3 reduced NF-κB activation and cytokine induction in the early stages of Staphylococcus aureus infection. Expression of cytokine genes induced by Staphylococcus aureus was not inhibited by a caspase-1 inhibitor, and did not occur through an autocrine mechanism in response to newly synthesized cytokines. We also demonstrated that NLRP3 could activate NF-κB and induce cytokines in response to sterile signals, monosodium urate crystals and aluminum adjuvant. Thus, NLRP3 mediates NF-κB activation in both sterile and microbially induced inflammation. Our findings show that not only does NLRP3 activate caspase-1 post-translationally, but it also induces multiple cytokine genes in the innate immune system.
authors.affiliation: Division of Immunology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kakumamachi, Kanazawa, Ishikawa, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kinoshita
authors.affiliation: Division of Immunology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kakumamachi, Kanazawa, Ishikawa, Japan.
authors.forename: Ryu
authors.initials: R
authors.lastname: Imamura
authors.affiliation: Division of Immunology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kakumamachi, Kanazawa, Ishikawa, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kushiyama
authors.affiliation: Division of Immunology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kakumamachi, Kanazawa, Ishikawa, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Suda
mesh_terms: D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013203:Staphylococcal Infections / Q000276:immunology / Q000378:metabolism*; D014527:Uric Acid / Q000494:pharmacology
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D014527:Uric Acid; D020170:Caspase 1