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* Division of Gastroenterology and Nutrition, Children’s Hospital Boston, Harvard Medical School, Boston, MA 02115;
Institute of Immunology, Center of Physiology, Pathophysiology and Immunology, Medical University Vienna, Vienna, Austria; and
Department of Autoimmunity and Transplantation, Novartis Institutes for Biomedical Research (NIBR), Vienna, Austria
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Grants STARTY-156, SFB-F2304, and 19425 of the Austrian Science Fund as well as by Grant 10294 of the Austrian National Bank.
2 B.P. and S.R. contributed equally to this study.
3 Address correspondence and reprint requests to Dr. Herbert Strobl, Institute of Immunology, Medical University Vienna, Lazarettgasse 19, Vienna, Austria. E-mail address: herbert.strobl{at}meduniwien.ac.at
4 Abbreviations used in this paper: AhR, aryl hydrocarbon receptor; XRE, xenobiotic response element; TCDD, 2,3,7,8 tetrachlorodibenzo-p-dioxin; Treg, regulatory T cell; DC, dendritic cell; moDC, monocyte-derived DC; LC, Langerhans cell; SCF, stem cell factor; FLT3L, FMS-like tyrosine kinase 3 ligand; β-NF, β-naphtoflavone; sh, short hairpin; PAI-1, plasminogen activator inhibitor 1.
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