Laboratory of Ocular Cell Biology and Visual Science, Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
J Cell Mol Med. 2019 Oct;23(10):6785-6796. doi: 10.1111/jcmm.14559. Epub 2019 Jul 21.
Galectin-1/LGALS1 is a hypoxia-induced angiogenic factor associated with diabetic retinopathy (DR). Recently, we elucidated a hypoxia-independent pathway to produce galectin-1 in Müller glial cells stimulated by interleukin (IL)-1β. Here we revealed glucocorticoid receptor (GR)-mediated inhibitory mechanisms for Müller glial galectin-1/LGALS1 expression. Activator protein (AP)-1 site in the LGALS1 enhancer region, to which activating transcription factor2, c-Fos and c-Jun bind, was shown to be essential for IL-1β-induced galectin-1/LGALS1 expression in Müller cells. Ligand (dexamethasone or triamcinolone acetonide)-activated GR induced dual specificity phosphatase (DUSP)1 expression via the glucocorticoid response element and attenuated IL-1β-induced galectin-1/LGALS1 expression by reducing phosphorylation of these AP-1 subunits following AKT and extracellular signal-regulated kinase (ERK)1/2 deactivation. Moreover, activated GR also caused DUSP1-independent down-regulation of IL-1β-induced LGALS1 expression via its binding to AP-1. Administration of glucocorticoids to mice attenuated diabetes-induced retinal galectin-1/Lgals1 expression together with AKT/AP-1 and ERK/AP-1 pathways. Supporting these in vitro and in vivo findings, immunofluorescence analyses showed co-localization of galectin-1 with GR and phosphorylated AP-1 in DUSP1-positive glial cells in fibrovascular tissues from patients with DR. Our present data demonstrated the inhibitory effects of glucocorticoids on glial galectin-1 expression via DUSP1-dependent and -independent deactivation of AP-1 signalling (transactivation and transrepression), highlighting therapeutic implications for DR.
半乳糖凝集素-1（Galectin-1/LGALS1）是一种与糖尿病视网膜病变（DR）相关的低氧诱导的血管生成因子。最近，我们阐明了一种在白细胞介素（IL）-1β刺激的 Müller 胶质细胞中产生半乳糖凝集素-1 的低氧非依赖性途径。在这里，我们揭示了糖皮质激素受体（GR）介导的 Müller 胶质细胞半乳糖凝集素-1/LGALS1 表达的抑制机制。AP-1 结合蛋白（AP-1）位点位于 LGALS1 增强子区域，激活转录因子 2、c-Fos 和 c-Jun 结合于此，对于 IL-1β诱导的 Müller 细胞半乳糖凝集素-1/LGALS1 表达是必需的。配体（地塞米松或曲安奈德）激活的 GR 通过糖皮质激素反应元件诱导双重特异性磷酸酶（DUSP）1 的表达，并通过 AKT 和细胞外信号调节激酶（ERK）1/2 失活后降低这些 AP-1 亚基的磷酸化，减弱 IL-1β诱导的半乳糖凝集素-1/LGALS1 表达。此外，激活的 GR 还通过与 AP-1 结合，引起 DUSP1 非依赖性的 IL-1β诱导的 LGALS1 表达下调。给予糖皮质激素可减弱糖尿病小鼠视网膜半乳糖凝集素-1/Lgals1 表达，同时减弱 AKT/AP-1 和 ERK/AP-1 途径。支持这些体外和体内研究结果，免疫荧光分析显示在 DR 患者的纤维血管组织中，DUSP1 阳性胶质细胞中半乳糖凝集素-1 与 GR 和磷酸化的 AP-1 共定位。我们的研究结果表明，糖皮质激素通过 DUSP1 依赖性和非依赖性的 AP-1 信号（反式激活和反式抑制）失活抑制神经胶质细胞半乳糖凝集素-1 的表达，这突显了其对 DR 的治疗意义。
