Galuh Sekar, Faught Erin, Klaassen Ingeborg, Koorneef Lisa L, Brinks Joost, van Dijk Elon H C, Elewaut Dirk, Schlingemann Reinier O, Schaaf Marcel J M, Boon Camiel J F, Meijer Onno C
J Endocrinol. 2025 Jul 4;266(1). doi: 10.1530/JOE-24-0283. Print 2025 Jul 1.
The glucocorticoid receptor (GR) mediates many activating and repressive effects of glucocorticoids in multiple contexts. Glucocorticoids can robustly induce the transcriptionally active protein Zinc finger and BTB domain containing 16 (ZBTB16). We evaluated how cortisol-induced ZBTB16, in turn, affects various GR-mediated actions in human cells and in 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 knockout 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. Finally, ZBTB16 protein was strongly induced by dexamethasone in fibroblast-like synoviocytes derived from osteoarthritis patients. The data suggest that cortisol-induced ZBTB16 acts as an intracellular modulator of glucocorticoid action by limiting GR-mediated activating effects and enhancing repressive effects. This mechanism may facilitate a return to the initial cellular state after (proinflammatory) stimulation and enhance GR's anti-inflammatory effects. This mechanism is similar to that of 'dissociated' GR ligands and may guide drug development that aims to reduce side effects while retaining the clinical benefits of glucocorticoid treatment.
糖皮质激素受体（GR）在多种情况下介导糖皮质激素的许多激活和抑制作用。糖皮质激素能强烈诱导转录活性蛋白锌指和含BTB结构域蛋白16（ZBTB16）。我们评估了皮质醇诱导的ZBTB16如何反过来影响人类细胞和斑马鱼中各种GR介导的作用。我们发现，阻止ZBTB16的诱导会增强GR对人类内皮细胞屏障和斑马鱼幼虫血糖水平的依赖性作用。相反，zbtb16功能敲除消除了GR对斑马鱼幼虫炎症反应的依赖性作用。在mRNA水平上，zbtb16敲低增强了一部分GR靶基因的反式激活并减弱了反式抑制。最后，地塞米松在骨关节炎患者来源的成纤维样滑膜细胞中强烈诱导ZBTB16蛋白。数据表明，皮质醇诱导的ZBTB16通过限制GR介导的激活作用并增强抑制作用，作为糖皮质激素作用的细胞内调节剂。这种机制可能有助于在（促炎）刺激后恢复到初始细胞状态，并增强GR的抗炎作用。这种机制类似于“解离”GR配体的机制，可能指导旨在减少副作用同时保留糖皮质激素治疗临床益处的药物开发。
