title: Crosstalk between glucocorticoids and IL-4 modulates Ym1 expression in alternatively activated myeloid cells.
abstract: Airway epithelial cells induce a tolerogenic microenvironment by modulating immune cells in the lung. We recently showed that the supernatant of airway epithelial cells induces two marker genes of alternative activation, Ym1 and Ms4a8a, in respiratory myeloid cells. This induction was partially mediated by glucocorticoids, secreted by airway epithelial cells. In this study, we further investigated Ym1 and Ms4a8a regulation in alternatively activated myeloid cells in the presence of the TH2 cytokines IL-4 and IL-13. We show that Ym1 expression is boosted upon co-stimulation with airway epithelial cell supernatant and IL-4/IL-13, whereas Ms4a8a expression is down-regulated. This suggests that a crosstalk between IL-4/IL-13 and glucocorticoid signaling exists. Blocking protein synthesis indicated that dexamethasone-induced de novo protein synthesis is required for the interaction between glucocorticoid and IL-4 signaling regarding Ym1 regulation. Using reporter gene constructs, we demonstrate that the important regulatory region within the Ym1 promoter is found between -602bp and -969bp upstream of the start of translation. Bioinformatic analysis identified several glucocorticoid response elements (GREs) in this region. Further analysis identified overlapping but functionally active glucocorticoid receptor and STAT-6 binding sites, supporting the cooperative effect of glucocorticoids and IL-4 in the regulation of Ym1. These findings further prove the plasticity and complexity of alternatively activated myeloid cells and the importance of the local microenvironment. We believe that this regulation is of special importance in the pulmonary system, since both factors, glucocorticoids and IL-4/13, play a role in airway diseases such as asthma.
authors.affiliation: Department of Infectious Diseases, Medical Microbiology and Hygiene, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ng Kuet Leong
authors.affiliation: International Centre for Genetic Engineering and Biotechnology (ICGEB) & Institute of Infectious Disease and Molecular Medicine (IDM), Division of Immunology, University of Cape Town & South African Medical Research Council (SAMRC), South Africa.
authors.forename: Frank
authors.initials: F
authors.lastname: Brombacher
authors.affiliation: Department of Infectious Diseases, Medical Microbiology and Hygiene, University Hospital Heidelberg, 69120 Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL). Electronic address: alexander.dalpke@med.uni-heidelberg.de.
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Dalpke
authors.affiliation: Department of Infectious Diseases, Medical Microbiology and Hygiene, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Weitnauer
mesh_terms: D000818:Animals; D001665:Binding Sites; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005938:Glucocorticoids / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism*; D037102:Lectins / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D019948:Receptors, Interleukin-4 / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism; D020218:Response Elements; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D001619:beta-N-Acetylhexosaminidases / Q000235:genetics* / Q000378:metabolism
chemical_list: D005938:Glucocorticoids; D037102:Lectins; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; D015847:Interleukin-4; C429541:Chil3 protein, mouse; D001619:beta-N-Acetylhexosaminidases
keywords: Glucocorticoids; IL-4; M2; Macrophages; Ms4a8a; Ym1