Sekar Galuh1, Erin Faught2, Ingeborg Klaassen3, Lisa Koorneef4,5, Joost Brinks1, Elon HC van Dijk1, Dirk Elewaut4,6,7, Reinier Schlingemann3,8,9, Marcel Schaaf2, Camiel Boon1,8, Onno Meijer10
(1) Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands. (2) Institute of Biology Leiden, Leiden University, Leiden, The Netherlands. (3) Ocular Angiogenesis Group, Department of Ophthalmology, Amsterdam University Medical Center, Amsterdam, The Netherlands. (4) Molecular Immunology and Inflammation Unit, VIB-UGent, Zwijnaarde, Belgium. (5) Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands. (6) Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium. (7) Department of Rheumatology, Ghent University Hospital, Ghent, Belgium. (8) Department of Ophthalmology, Amsterdam University Medical Center, Amsterdam, The Netherlands. (9) Department of Ophthalmology, University of Lausanne, Jules Gonin Eye Hospital, Fondation Aisle des Aveugles, Lausanne, Switzerland. (10) Department of Medicine, Division of Endocrinology and Metabolism, Leiden University Medical Center, Leiden, The Netherlands.
The glucocorticoid receptor (GR) mediates many activating and repressive effects of glucocorticoids in multiple contexts. Glucocorticoids can robustly induce the transcriptionally active protein ZBTB16. However, the effects of GR-induced ZBTB16 on the GR transcriptional and functional activities are understudied. Here, we evaluated how cortisol-induced ZBTB16 affects various GR-mediated actions in human cells and zebrafish.
We found that prevention of ZBTB16 induction led to potentiated GR-dependent effects on the human endothelial cell barrier and blood glucose levels in zebrafish larvae. In contrast, zbtb16 functional knockdown abolished the GR-dependent effects on the inflammatory response in zebrafish larvae. At the mRNA level, zbtb16 knockdown potentiated transactivation and attenuated transrepression in a subset of GR target genes. Lastly, the ZBTB16 protein was strongly induced by dexamethasone in fibroblast-like synoviocytesderived from osteoarthritis patients.
The data suggest that cortisol-induced ZBTB16 limits GR-mediated activating effects and enhances repressive effects, acting as an intracellular modulator of glucocorticoid action. In the inflammatory setting, cortisol-induced ZBTB16 enhances GR’s anti-inflammatory effects and may facilitate the cells to return to the initial state. This mechanism is similar to ‘dissociated’ GR ligands and may guide drug development that aims to reduce side effects while retaining the clinical benefits of glucocorticoid treatment.