title: DC-SCRIPT regulates glucocorticoid receptor function and expression of its target GILZ in dendritic cells.
abstract: Dendritic cells (DCs) play a central role in the immune system; they can induce immunity or tolerance depending on diverse factors in the DC environment. Pathogens, but also tissue damage, hormones, and vitamins, affect DC activation and maturation. In particular, glucocorticoids (GCs) are known for their immunosuppressive effect on DCs, creating tolerogenic DCs. GCs activate the type I nuclear receptor (NR) glucocorticoid receptor (GR), followed by induced expression of the transcription factor glucocorticoid-inducible leucine zipper (GILZ). GILZ has been shown to be necessary and sufficient for GC-induced tolerogenic DC generation. Recently, we have identified the DC-specific transcript (DC-SCRIPT) as an NR coregulator, suppressing type I steroid NRs estrogen receptor and progesterone receptor. In this study, we analyzed the effect of DC-SCRIPT on GR activity. We demonstrate that DC-SCRIPT coexists with GR in protein complexes and functions as a corepressor of GR-mediated transcription. Coexpression of DC-SCRIPT and GR is shown in human monocyte-derived DCs, and DC-SCRIPT knockdown enhances GR-dependent upregulation of GILZ mRNA expression in DCs. This demonstrates that DC-SCRIPT serves an important role in regulating GR function in DCs, corepressing GR-dependent upregulation of the tolerance-inducing transcription factor GILZ. These data imply that by controlling GR function and GILZ expression DC-SCRIPT is potentially involved in the balance between tolerance and immunity.
authors: Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands.
authors: Saartje
authors: S
authors: Hontelez
authors: Nina
authors: N
authors: Karthaus
authors: Maaike W
authors: MW
authors: Looman
authors: Marleen
authors: M
authors: Ansems
authors: Gosse J
authors: GJ
authors: Adema
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D047468:Immunoprecipitation; D016350:Leucine Zippers / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D059368:RNA Isoforms; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D002352:Carrier Proteins; D059368:RNA Isoforms; D011965:Receptors, Glucocorticoid; C515832:ZNF366 protein, human