title: An anti-inflammatory property of Candida albicans β-glucan: Induction of high levels of interleukin-1 receptor antagonist via a Dectin-1/CR3 independent mechanism.
abstract: BACKGROUND
  Candida albicans is an opportunistic fungal pathogen that induces strong proinflammatory responses, such as IL-1β production. Much less is known about the induction of immune modulatory cytokines, such as the IL-1 receptor antagonist (IL-1Ra) that is the main natural antagonist of IL-1, by C. albicans.
  
  
  METHODS
  Peripheral blood mononuclear cells (PBMC) of healthy individuals were stimulated with C. albicans and different components of the fungal cell wall. The role of pathogen recognition receptors (PRRs) for the induction of IL-1β and IL-1Ra was investigated by using specific blockers or in PBMC from Dectin-1 deficient patients.
  
  
  RESULTS
  C. albicans induced a strong IL-1Ra response, and this induction was primarily induced by the cell-wall component β-glucan. Blocking IL-1Ra significantly increased C. albicans β-glucan hyphae induced IL-1β and IL-6 production. Surprisingly, blocking the β-glucan receptor Dectin-1 or the downstream Syk or Raf-1 pathways only marginally reduced C. albicans-induced IL-1Ra production, while blocking of the complement receptor 3 (CR3), TLR2 or TLR4 had no effect. In line with this, blocking MAP kinases had little effect on Candida-induced IL-1Ra production. PBMC isolated from Dectin-1 deficient patients produced normal IL-1Ra amounts in response to C. albicans stimulation. Interestingly, the IL-1Ra synthesis induced by β-glucan was blocked by inhibitors of the Akt/PI3K pathway.
  
  
  CONCLUSIONS
  β-glucan of C. albicans induces a strong IL-1Ra response, which is independent of the β-glucan receptors dectin-1 and CR3. These data strongly argue for the existence of an unknown β-glucan receptor that specifically induces an Akt/PI3K-dependent anti-inflammatory IL-1Ra response upon recognition of C. albicans.
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Nijmegen Institute for Infection, Inflammation, and Immunity (N4i), Nijmegen, The Netherlands.
authors.forename: Sanne P
authors.initials: SP
authors.lastname: Smeekens
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Nijmegen Institute for Infection, Inflammation, and Immunity (N4i), Nijmegen, The Netherlands.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Gresnigt
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Nijmegen Institute for Infection, Inflammation, and Immunity (N4i), Nijmegen, The Netherlands.
authors.forename: Katharina L
authors.initials: KL
authors.lastname: Becker
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Nijmegen Institute for Infection, Inflammation, and Immunity (N4i), Nijmegen, The Netherlands.
authors.forename: Shih-Chin
authors.initials: SC
authors.lastname: Cheng
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Nijmegen Institute for Infection, Inflammation, and Immunity (N4i), Nijmegen, The Netherlands.
authors.forename: Stejara A
authors.initials: SA
authors.lastname: Netea
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Nijmegen Institute for Infection, Inflammation, and Immunity (N4i), Nijmegen, The Netherlands.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Jacobs
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Nijmegen Institute for Infection, Inflammation, and Immunity (N4i), Nijmegen, The Netherlands.
authors.forename: Trees
authors.initials: T
authors.lastname: Jansen
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Nijmegen Institute for Infection, Inflammation, and Immunity (N4i), Nijmegen, The Netherlands.
authors.forename: Frank L
authors.initials: FL
authors.lastname: van de Veerdonk
authors.affiliation: Department of Surgery, Quillen College of Medicine, East Tennessee State University, TN, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Williams
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Nijmegen Institute for Infection, Inflammation, and Immunity (N4i), Nijmegen, The Netherlands.
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Department of Medicine, University of Colorado, Denver, CO, USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Nijmegen Institute for Infection, Inflammation, and Immunity (N4i), Nijmegen, The Netherlands. Electronic address: m.netea@aig.umcn.nl.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
mesh_terms: D002176:Candida albicans / Q000276:immunology* / Q000502:physiology; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type / Q000276:immunology* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D016177:Macrophage-1 Antigen / Q000276:immunology* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D047071:beta-Glucans / Q000276:immunology*; D000099181:Dectin-1
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D037181:Lectins, C-Type; D016177:Macrophage-1 Antigen; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D047071:beta-Glucans; C546929:CLEC7A protein, human; D000099181:Dectin-1
keywords: Candida albicans; IL-1Ra; β-Glucan