title: Malassezia-derived indoles activate the aryl hydrocarbon receptor and inhibit Toll-like receptor-induced maturation in monocyte-derived dendritic cells.
abstract: BACKGROUND
  The aryl hydrocarbon receptor (AhR) is a nuclear receptor and transcriptional regulator with pleiotropic effects. The production of potent AhR ligands by Malassezia yeasts, such as indirubin, indolo[3,2-b]carbazole (ICZ), tryptanthrin and malassezin, has been associated with the pathogenesis of seborrhoeic dermatitis and pityriasis versicolor. Antigen-presenting cells in the skin can encounter microbes in the presence of these bioactive metabolites that could potentially modulate their function.
  
  
  OBJECTIVE
  To study the effects of the aforementioned naturally occurring ligands on AhR activation and Toll-like receptor (TLR)-induced maturation in human monocyte-derived dendritic cells (moDCs).
  
  
  METHODS
  These indoles were screened for AhR activation capacity in moDCs employing CYP1A1 and CYP1B1 induction as read out and for their effects on the function of moDCs after TLR-ligand stimulation.
  
  
  RESULTS
  Indirubin and ICZ were the most potent AhR ligands and were selected for subsequent experiments. Concurrent exposure of moDCs to indirubin or ICZ together with TLR agonists significantly augmented the AhR-mediated CYP1A1 and CYP1B1 gene expression. Additionally, mature DCs that were subsequently stimulated with AhR ligands showed increased AhR target gene expression. Moreover, these ligands limited TLR-induced phenotypic maturation (CD80, CD83, CD86, MHC II upregulation) of moDCs, reduced secretion of the inflammatory cytokines interleukin (IL)-6 and IL-12, and decreased their ability to induce alloreactive T-lymphocyte proliferation.
  
  
  CONCLUSIONS
  These results demonstrate that AhR agonists of yeast origin are able to inhibit moDC responses to TLR ligands and that moDCs can adapt through increased transcription of metabolizing enzymes such as CYP1A1 and CYP1B1.
authors.affiliation: Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Po Box 9101, 6500 HB Nijmegen, the Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Vlachos
authors.forename: B M
authors.initials: BM
authors.lastname: Schulte
authors.forename: P
authors.initials: P
authors.lastname: Magiatis
authors.forename: G J
authors.initials: GJ
authors.lastname: Adema
authors.forename: G
authors.initials: G
authors.lastname: Gaitanis
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D018664:Interleukin-12 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008290:Malassezia; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects*; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors*
chemical_list: D002227:Carbazoles; D007211:Indoles; D015850:Interleukin-6; D011799:Quinazolines; D018336:Receptors, Aryl Hydrocarbon; D051193:Toll-Like Receptors; C436511:malassezin; C046243:tryptanthrine; D018664:Interleukin-12; C075954:indolo(3,2-b)carbazole; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; C027185:indirubin