Reciprocal role of GATA-1 and vitamin D receptor in human myeloid dendritic cell differentiation

• Published in: Blood Vol. 114; no. 18; pp. 3813 - 3821
• Main Authors: Göbel, Florian, Taschner, Sabine, Jurkin, Jennifer, Konradi, Sabine, Vaculik, Christine, Richter, Susanne, Kneidinger, Doris, Mühlbacher, Christina, Bieglmayer, Christian, Elbe-Bürger, Adelheid, Strobl, Herbert
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.10.2009
• Subjects: Cell Differentiation - drug effects; Cell Differentiation - immunology; Dendritic Cells - cytology; Dendritic Cells - immunology; Dendritic Cells - metabolism; GATA1 Transcription Factor - genetics; GATA1 Transcription Factor - immunology; GATA1 Transcription Factor - metabolism; Gene Knockdown Techniques; Humans; Interleukin-4 - genetics; Interleukin-4 - immunology; Interleukin-4 - pharmacology; K562 Cells; Lipopolysaccharide Receptors; Monocytes - cytology; Monocytes - immunology; Monocytes - metabolism; Myeloid Progenitor Cells - cytology; Myeloid Progenitor Cells - immunology; Myeloid Progenitor Cells - metabolism; Receptors, Calcitriol - genetics; Receptors, Calcitriol - immunology; Receptors, Calcitriol - metabolism; Repressor Proteins - genetics; Repressor Proteins - immunology; Repressor Proteins - metabolism; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - immunology; Transforming Growth Factor beta1 - pharmacology; U937 Cells
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-03-210484

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 D3 receptor (VDR) is induced by transforming growth factor β1 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 β1 and is functionally involved in promoting LC differentiation.