title: Bypassing pathogen-induced inflammasome activation for the regulation of interleukin-1beta production by the fungal pathogen Candida albicans.
abstract: BACKGROUND
  Interleukin (IL)-1beta has an important role in antifungal defense mechanisms. The inflammasome is thought to be required for caspase-1 activation and processing of the inactive precursor pro-IL-1beta. The aim of the present study was to investigate the pathways of IL-1beta production induced by Candida albicans in human monocytes.
  
  
  METHODS
  Human mononuclear cells were stimulated with C. albicans or mutant strains defective in mannosylation or chitin. Receptors were blocked with specific antagonists, and the IL-1beta concentration was measured.
  
  
  RESULTS
  Human primary monocytes produce bioactive IL-1beta when stimulated with C. albicans. The transcription of IL-1beta was induced through mannose receptor (MR), Toll-like receptor (TLR) 2, and dectin-1 but not through TLR4 and TLR9. N-mannan-linked residues, chitin, and beta-glucan from C. albicans are important for IL-1beta stimulation. Surprisingly, processing and secretion of IL-1beta in monocytes did not require pathogen-mediated inflammasome activation, because of the constitutive activation of caspase-1 and the capability of monocytes to release endogenous adenosine-5'-triphosphate.
  
  
  CONCLUSIONS
  This study is the first dissection of the molecular mechanisms of IL-1beta production by a fungal pathogen. Transcription through mannan/chitin/MR and beta-glucan/dectin-1/TLR2 induces production of IL-1beta by C. albicans in human monocytes, whereas processing of IL-1beta is mediated by constitutively active caspase-1.
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Frank L
authors.initials: FL
authors.lastname: van de Veerdonk
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Isabel
authors.initials: I
authors.lastname: Devesa
authors.forename: Héctor M
authors.initials: HM
authors.lastname: Mora-Montes
authors.forename: Thirumala-Devi
authors.initials: TD
authors.lastname: Kanneganti
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
authors.forename: Neil A R
authors.initials: NA
authors.lastname: Gow
authors.forename: Bart Jan
authors.initials: BJ
authors.lastname: Kullberg
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002176:Candida albicans / Q000276:immunology / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism* / Q000382:microbiology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein
chemical_list: D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D053583:Interleukin-1beta; C512299:Ipaf protein, mouse; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D020170:Caspase 1