title: 1,25-dihydroxyvitamin D3 modulates cytokine production induced by Candida albicans: impact of seasonal variation of immune responses.
abstract: BACKGROUND
  Our interest in immunological effects produced by vitamin D(3) (1,25(OH)(2)D(3)) and its therapeutic potential prompted us to examine the role of 1,25(OH)(2)D(3) on cytokine production by Candida albicans.
  
  
  METHODS
  Peripheral blood mononuclear cells (PBMC) with stimulated C. albicans and 1,25(OH)(2)D(3), cytokine concentrations were measured in supernatant. Quantitative polymerase chain reaction (qPCR) was performed for T cell transcription factors, SOCS1 and 3. TLR2/4, Dectin-1, and mannose receptor expression was studied using flow cytometry and qPCR. An ex-vivo stimulation study was carried out in healthy volunteers to investigate the seasonality of immune response to C. albicans.
  
  
  RESULTS
  Upon in vitro C. albicans stimulation, 1,25(OH)(2)D(3) induced a dose-dependent, down-regulation of IL-6, TNFα, IL-17, and IFNγ. It also increased IL-10 production. The shift in cytokine profile was not due to 1,25(OH)(2)D(3) augmenting expression of either Thelper differentiation factors or SOCS1 and SOCS3 mRNA. 1,25(OH)(2)D(3) inhibited TLR2, TLR4, Dectin-1, and MR mRNA and protein expression. In our seasonality study, both IL-17 and IFNγ levels were suppressed in summer when 25(OH)D(3) levels were elevated.
  
  
  CONCLUSIONS
  Vitamin D(3) skews cytokine responses toward an antiinflammatory profile, mediated by suppression of TLR2, TLR4, Dectin-1, and MR transcription, leading to reduced surface expression. The biological relevance of these effects has been confirmed by the seasonality of cytokine responses.
authors.affiliation: Department of Laboratory Medicine, Radboud University Nijmegen Medical Center; 3Nijmegen Institute for Infection, Inflammation and Immunity, Nijmegen, The Netherlands.
authors.forename: Ai-Leng
authors.initials: AL
authors.lastname: Khoo
authors.forename: Louis Y A
authors.initials: LY
authors.lastname: Chai
authors.forename: Hans J P M
authors.initials: HJ
authors.lastname: Koenen
authors.forename: Bart-Jan
authors.initials: BJ
authors.lastname: Kullberg
authors.forename: Irma
authors.initials: I
authors.lastname: Joosten
authors.forename: André J A M
authors.initials: AJ
authors.lastname: van der Ven
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
mesh_terms: D000328:Adult; D002117:Calcitriol / Q000494:pharmacology*; D002176:Candida albicans / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D037181:Lectins, C-Type / Q000032:analysis; D007963:Leukocytes, Mononuclear / Q000737:chemistry / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000032:analysis; D008565:Membrane Proteins / Q000032:analysis; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000032:analysis; D011956:Receptors, Cell Surface / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012621:Seasons; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000032:analysis; D051195:Toll-Like Receptor 2 / Q000032:analysis; D051197:Toll-Like Receptor 4 / Q000032:analysis; D000099181:Dectin-1
chemical_list: D002117:Calcitriol; D016207:Cytokines; D007155:Immunologic Factors; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D000099181:Dectin-1; C108944:SOCS1 protein, human; C106644:SOCS3 protein, human