Crosstalk between glucocorticoids and IL-4 modulates Ym1 expression in alternatively activated myeloid cells |
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| Affiliation: | 1. Department of Infectious Diseases, Medical Microbiology and Hygiene, University Hospital Heidelberg, 69120 Heidelberg, Germany;2. 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;3. Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL);1. Department of Pathology and Immunology, Baylor College of Medicine, Houston, Tex;2. Department of Medicine, Baylor College of Medicine, Houston, Tex;3. Department of Pediatrics, Baylor College of Medicine, Houston, Tex;4. Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea;5. Channing laboratory Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass;1. Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China;2. Department of Pathology, Affiliated Hospital of Guilin Medical University, Guilin, China;3. Henan Key Laboratory of Tumour Pathology, Department of Pathology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China;4. Department of Pathology, The Second Affiliated Hospital, Sun Yat-sen University, Guangzhou, China;5. Department of Pathology, Guangzhou First Municipal People''s Hospital, Guangzhou, China;6. Department of Gastroenterology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China;1. Reynolds American, Inc. 401 N. Main St., Winston Salem, NC 27101, United States;2. Immunity, Inflammation and Disease Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, United States;3. Galaxy Diagnostics, Inc. 7020 Kit Creek Rd., Ste 130, Research Triangle Park, NC 27709, United States;4. Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695, United States |
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| 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 −602 bp and −969 bp 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. |
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| Keywords: | Glucocorticoids Ym1 Ms4a8a Macrophages IL-4 M2 |
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