Spinelli Sherry L, Xi Xia, McMillan David H, Woeller Collynn F, Richardson Mary E, Cavet Megan E, Zhang Jin-Zhong, Feldon Steven E, Phipps Richard P
Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
Department of Ophthalmology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
Exp Eye Res. 2014 Oct;127:290-8. doi: 10.1016/j.exer.2014.07.013.
Selective glucocorticoid receptor agonists (SEGRAs) are a new class of compounds under clinical evaluation for treatment of ocular inflammation. Widely prescribed therapeutics, such as glucocorticoids, are effective at reducing ocular inflammation, but their long term use predisposes to undesirable side effects. The purpose of this study was to investigate a novel SEGRA, mapracorat (BOL-303242-X), and the differences in mapracorat's mechanism of action compared with traditional steroids (i.e. dexamethasone). Keratocytes from three different humans were cultured and treated with mapracorat or dexamethasone, with and without a strong provoking agent, interleukin (IL)-1β. The effects of mapracorat compared to dexamethasone were determined by measuring protein levels (Western blotting) and DNA binding (ELISA) for two nuclear factor-kappaB (NF-κB) family members, RelA and RelB. Cytokine production (i.e. IL-6, IL-8, prostaglandin E2 (PGE2)) was characterized by immunoassay. Our findings reveal mechanistic differences between mapracorat and traditional steroid therapies. Mapracorat showed partial attenuation of the classical NF-κB pathway, consistent with traditional steroids. However, mapracorat uniquely potentiated a novel anti-inflammatory mechanism through rapid upregulation of RelB, an anti-inflammatory member of the NF-κB alternative pathway. Mapracorat potently inhibits ocular inflammation in vitro and is a promising new treatment for ocular inflammatory disease. Mapracorat acts, in part, by a novel mechanism via upregulation of RelB in the NF-κB alternative pathway.
选择性糖皮质激素受体激动剂（SEGRAs）是一类正在进行临床评估用于治疗眼部炎症的新型化合物。广泛使用的治疗药物，如糖皮质激素，在减轻眼部炎症方面有效，但长期使用易引发不良副作用。本研究的目的是调查一种新型SEGRA，马普拉考特（BOL-303242-X），并比较马普拉考特与传统类固醇（即地塞米松）作用机制的差异。培养来自三个不同人的角膜细胞，并用马普拉考特或地塞米松进行处理，同时添加或不添加强效刺激剂白细胞介素（IL）-1β。通过测量两种核因子-κB（NF-κB）家族成员RelA和RelB的蛋白质水平（蛋白质印迹法）和DNA结合（酶联免疫吸附测定）来确定马普拉考特与地塞米松相比的效果。通过免疫测定法对细胞因子产生（即IL-6、IL-8、前列腺素E2（PGE2））进行表征。我们的研究结果揭示了马普拉考特与传统类固醇疗法之间的作用机制差异。马普拉考特显示出经典NF-κB途径的部分减弱，这与传统类固醇一致。然而，马普拉考特通过快速上调RelB（NF-κB替代途径的抗炎成员）独特地增强了一种新的抗炎机制。马普拉考特在体外能有效抑制眼部炎症，是一种有前景的眼部炎性疾病新疗法。马普拉考特部分通过一种新机制起作用，即上调NF-κB替代途径中的RelB。
