| Title | Glucocorticoids mobilize macrophages by transcriptionally up-regulating the exopeptidase DPP4 |
|---|---|
| Publication Type | Articolo su Rivista peer-reviewed |
| Year of Publication | 2020 |
| Authors | Diaz-Jimenez, David, Petrillo Maria Grazia, Busada Jonathan T., Hermoso Marcela A., and Cidlowski John A. |
| Journal | Journal of Biological Chemistry |
| Volume | 295 |
| Pagination | 3213 – 3227 |
| Type of Article | Article |
| ISSN | 00219258 |
| Keywords | animal, animal cell, Animals, Anti-inflammatories, article, bone marrow derived macrophage, cell differentiation, cell migration assay, cell motility, cell motion, Cell Movement, cell stimulation, chemistry, controlled study, cytology, dexamethasone, Dipeptidyl peptidase, Dipeptidyl Peptidase 4, dipeptidyl peptidase IV, DPP4 gene, DPP4 protein, drug effect, enzyme activity, gene, Gene expression patterns, gene expression regulation, gene interaction, gene knockdown, Gene transcriptions, Genetic, genetic conservation, genetic transcription, genetics, glucocorticoid, glucocorticoid receptor, glucocorticoid response element, Glucocorticoids, hormone responsive element, Hormones, human, human cell, Humans, Inflammatory disease, Inflammatory disorders, Linagliptin, macrophage, macrophage migration, Macrophages, metabolism, Mice, monocyte, Monocytes, mouse, murine, nonhuman, Peritoneal macrophage, peritoneum macrophage, priority journal, promoter region, Promoter Regions, Receptors, Regulatory Elements, regulatory sequence, RNA, RNA Interference, sitagliptin, Sitagliptin Phosphate, Small Interfering, Small interfering RNA, THP-1 cell line, THP-1 Cells, Tissue homeostasis, Transcription, transcription regulation, Transcriptional, transcriptome, Up-Regulation, upregulation |
| Abstract | Glucocorticoids are potent endogenous anti-inflammatory molecules, and their cognate receptor, glucocorticoid receptor (GR), is expressed in nearly all immune cells. Macrophages are heterogeneous immune cells having a central role in both tissue homeostasis and inflammation and also play a role in the pathogenesis of some inflammatory diseases. Paradoxically, glucocorticoids have only a limited efficacy in controlling the resolution of these macrophage-related diseases. Here, we report that the transcriptomes of monocyte-like THP-1 cells and macrophage-like THP-1 cells (THP1-MΦ) have largely conserved gene expression patterns. In contrast, the differentiation to THP1-MΦ significantly altered the sensitivity of gene transcription to glucocorticoids. Among glucocorticoid-regulated genes, we identified the exopeptidase dipeptidyl peptidase-4 (DPP4) as a critical glucocorticoid-responsive gene in THP1-MΦ. We found that GR directly induces DPP4 gene expression by binding to two glucocorticoid-responsive elements (GREs) within the DPP4 promoter. Additionally, we show that glucocorticoid-induced DPP4 expression is blocked by the GR antagonist RU-486 and by GR siRNA transfection and that DPP4 enzyme activity is reduced by DPP4 inhibitors. Of note, glucocorticoids highly stimulated macrophage mobility; unexpectedly, DPP4 mediated the glucocorticoid-induced macrophage migration, and siRNA-mediated knockdowns of GR and DPP4 blocked dexamethasone-induced THP1-MΦ migration. Moreover, glucocorticoid-induced DPP4 activation was also observed in proinflammatory M1-polarized murine macrophages, as well as peritoneal macrophages, and was associated with increased macrophage migration. Our results indicate that glucocorticoids directly up-regulate DPP4 expression and thereby induce migration in macrophages, potentially explaining why glucocorticoid therapy is less effective in controlling macrophage-dominated inflammatory disorders. © 2020 American Society for Biochemistry and Molecular Biology Inc.. All rights reserved. |
| Notes | Cited by: 25; All Open Access, Green Open Access, Hybrid Gold Open Access |
| URL | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85081051832&doi=10.1074%2fjbc.RA119.010894&partnerID=40&md5=2c29e12b47ed0ab7c461e91b94108bbb |
| DOI | 10.1074/jbc.RA119.010894 |
| Citation Key | Diaz-Jimenez20203213 |
| PubMed ID | 31988243 |
