title: Aryl hydrocarbon receptor activation inhibits in vitro differentiation of human monocytes and Langerhans dendritic cells.
abstract: The transcription factor aryl hydrocarbon receptor (AhR) represents a promising therapeutic target in allergy and autoimmunity. AhR signaling induced by the newly described ligand VAF347 inhibits allergic lung inflammation as well as suppresses pancreatic islet allograft rejection. These effects are likely mediated via alterations in dendritic cell (DC) function. Moreover, VAF347 induces tolerogenic DCs. Langerhans cells (LCs) are immediate targets of exogenous AhR ligands at epithelial surfaces; how they respond to AhR ligands remained undefined. We studied AhR expression and function in human LCs and myelopoietic cell subsets using a lineage differentiation and gene transduction model of human CD34(+) hematopoietic progenitors. We found that AhR is highly regulated during myeloid subset differentiation. LCs expressed highest AhR levels followed by monocytes. Conversely, neutrophil granulocytes lacked AhR expression. AhR ligands including VAF347 arrested the differentiation of monocytes and LCs at an early precursor cell stage, whereas progenitor cell expansion or granulopoiesis remained unimpaired. AhR expression was coregulated with the transcription factor PU.1 during myeloid subset differentiation. VAF347 inhibited PU.1 induction during initial monocytic differentiation, and ectopic PU.1 restored monocyte and LC generation in the presence of this compound. AhR ligands failed to interfere with cytokine receptor signaling during LC differentiation and failed to impair LC activation/maturation. VAF347-mediated antiproliferative effect on precursors undergoing LC lineage differentiation occurred in a clinically applicable serum-free culture model and was not accompanied by apoptosis induction. In conclusion, AhR agonist signaling interferes with transcriptional processes leading to monocyte/DC lineage commitment of human myeloid progenitor cells.
authors.affiliation: Children's Hospital Boston, Harvard Medical School, MA 02115, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Platzer
authors.forename: Susanne
authors.initials: S
authors.lastname: Richter
authors.forename: Doris
authors.initials: D
authors.lastname: Kneidinger
authors.forename: Darina
authors.initials: D
authors.lastname: Waltenberger
authors.forename: Maximilian
authors.initials: M
authors.lastname: Woisetschläger
authors.forename: Herbert
authors.initials: H
authors.lastname: Strobl
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D019070:Cell Lineage / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006131:Growth Inhibitors / Q000494:pharmacology / Q000502:physiology; D006801:Humans; D020014:K562 Cells; D007801:Langerhans Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology
chemical_list: D006131:Growth Inhibitors; D011743:Pyrimidines; D018336:Receptors, Aryl Hydrocarbon; C509596:VAF347