Bypassing pathogen-induced inflammasome activation for the regulation of interleukin-1β production by the fungal pathogen Candida albicans

Frank L van de Veerdonk, Leo A B Joosten, Isabel Devesa, Hector M Mora-Montes, Thirumala-Devi Kanneganti, Charles A Dinarello, Jos W M Van Der Meer, Neil A R Gow, Bart Jan Kullberg, Mihai G Netea

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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.
Original languageEnglish
Pages (from-to)1087-1096
Number of pages10
JournalThe journal of infectious diseases
Volume199
Issue number7
DOIs
Publication statusPublished - 1 Apr 2009

Keywords

  • animals
  • apoptosis regulatory proteins
  • calcium-binding proteins
  • Candida albicans
  • carrier proteins
  • caspase 1
  • cells, cultured
  • humans
  • inflammation
  • interleukin-1beta
  • leukocytes, mononuclear
  • macrophages
  • mice

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    van de Veerdonk, F. L., Joosten, L. A. B., Devesa, I., Mora-Montes, H. M., Kanneganti, T-D., Dinarello, C. A., Van Der Meer, J. W. M., Gow, N. A. R., Kullberg, B. J., & Netea, M. G. (2009). Bypassing pathogen-induced inflammasome activation for the regulation of interleukin-1β production by the fungal pathogen Candida albicans. The journal of infectious diseases, 199(7), 1087-1096. https://doi.org/10.1086/597274