title: Reciprocal role of GATA-1 and vitamin D receptor in human myeloid dendritic cell differentiation.
abstract: Two major pathways of human myeloid dendritic cell (DC) subset differentiation have previously been delineated. Langerhans cells (LCs) reside in epithelia in the steady state, whereas monocytes can provide dendritic cells (DCs) on demand in response to inflammatory signals. Both DC subset pathways arise from shared CD14+ monocyte precursors, which in turn develop from myeloid committed progenitor cells. However, the underlying hematopoietic mechanisms still remain poorly defined. Here, we demonstrate that the vitamin D(3) receptor (VDR) is induced by transforming growth factor beta1 during LC lineage commitment and exerts a positive role during LC generation. In contrast, VDR is repressed during interleukin-4 (IL-4)-dependent monocyte-derived DC (moDC) differentiation. We identified GATA-1 as a repressor of VDR. GATA-1 is induced by IL-4 in moDCs. Forced inducible expression of GATA-1 mimics IL-4 in redirecting moDC differentiation and vice versa, GATA-1 knockdown arrests moDC differentiation at the monocyte stage. Moreover, ectopic GATA-1 expression stabilizes the moDC phenotype under monocyte-promoting conditions in the presence of vitamin D3 (VD3). In summary, human myeloid DC subset differentiation is inversely regulated by GATA-1 and VDR. GATA-1 mediates the repression of VDR and enables IL-4-dependent moDC differentiation. Conversely, VDR is induced downstream of transforming growth factor beta1 and is functionally involved in promoting LC differentiation.
authors.affiliation: Institute of Immunology, Center of Physiology, Pathophysiology, and Immunology, Medical University of Vienna, Vienna, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Göbel
authors.forename: Sabine
authors.initials: S
authors.lastname: Taschner
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jurkin
authors.forename: Sabine
authors.initials: S
authors.lastname: Konradi
authors.forename: Christine
authors.initials: C
authors.lastname: Vaculik
authors.forename: Susanne
authors.initials: S
authors.lastname: Richter
authors.forename: Doris
authors.initials: D
authors.lastname: Kneidinger
authors.forename: Christina
authors.initials: C
authors.lastname: Mühlbacher
authors.forename: Christian
authors.initials: C
authors.lastname: Bieglmayer
authors.forename: Adelheid
authors.initials: A
authors.lastname: Elbe-Bürger
authors.forename: Herbert
authors.initials: H
authors.lastname: Strobl
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D020014:K562 Cells; D018950:Lipopolysaccharide Receptors; D009000:Monocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D020298:U937 Cells
chemical_list: D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; C508598:IL4 protein, human; D018950:Lipopolysaccharide Receptors; D018167:Receptors, Calcitriol; D012097:Repressor Proteins; D053773:Transforming Growth Factor beta1; D015847:Interleukin-4