Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai 200080, China.
Cell Death Dis. 2017 Oct 12;8(10):e3115. doi: 10.1038/cddis.2017.502.
Amyloid-beta (Aβ) is a hallmark component of age-related macular degeneration (AMD), which induces secretion of pro-inflammatory cytokines from retinal pigment epithelium (RPE). Previous studies have shown that p50/RelA (p65), a member of NF-κB family, is an essential pro-inflammatory transcription factor responding to Aβ stimulation, but few focused on the other two Rel transcription factor members - RelB and c-Rel - and their role in Aβ-mediated inflammation. It was reported that RelA, RelB and c-Rel are also implicated in various NF-κB-mediated inflammatory diseases. Therefore, we infer that Aβ-mediated inflammation targets not only the classical inflammation regulator, RelA, but also RelB and c-Rel. In this study, we demonstrate that intravitreally injected Aβ mice develop AMD-like pathologic changes, coupled with Rel protein (RelA, RelB and c-Rel) synthesis and nuclear translocation. To focus on the interaction mechanism of Rel proteins, we found that RelB and c-Rel formed a heterodimer with RelA in mice model. We also found that c-Rel silencing decreased the levels of Aβ-dependent RelA expression, indicating that RelB and c-Rel may interact with RelA as coactivator and c-Rel is required to activate the expression of RelA. Moreover, Rel protein silencing decreased the expression of distinct pro-inflammatory cytokines. Together, we demonstrate that besides RelA, RelB and c-Rel can also be activated by Aβ, all of which mediate pro-inflammatory cytokine transcription and RPE damage. Our findings imply that RPE-mediated inflammation under the stimulation of Aβ is multi-targeted and RelA, RelB and c-Rel proteins may be the new targets of anti-inflammatory agents.
淀粉样蛋白-β（Aβ）是年龄相关性黄斑变性（AMD）的标志性成分，可诱导视网膜色素上皮（RPE）分泌促炎细胞因子。先前的研究表明，p50/RelA（p65），NF-κB 家族的成员，是对 Aβ刺激作出反应的必需促炎转录因子，但很少有研究集中在另外两个 Rel 转录因子成员 RelB 和 c-Rel 及其在 Aβ介导的炎症中的作用。有报道称，RelA、RelB 和 c-Rel 也与各种 NF-κB 介导的炎症性疾病有关。因此，我们推断 Aβ 介导的炎症不仅针对经典炎症调节剂 RelA，还针对 RelB 和 c-Rel。在这项研究中，我们证明了玻璃体内注射 Aβ的小鼠会发展出类似 AMD 的病理变化，同时伴有 Rel 蛋白（RelA、RelB 和 c-Rel）的合成和核转位。为了关注 Rel 蛋白的相互作用机制，我们在小鼠模型中发现 RelB 和 c-Rel 与 RelA 形成异二聚体。我们还发现 c-Rel 沉默降低了 Aβ依赖性 RelA 表达水平，表明 RelB 和 c-Rel 可能作为共激活子与 RelA 相互作用，并且 c-Rel 是激活 RelA 表达所必需的。此外，Rel 蛋白沉默降低了不同促炎细胞因子的表达。综上所述，我们证明了除了 RelA 之外，RelB 和 c-Rel 也可以被 Aβ激活，它们都介导促炎细胞因子的转录和 RPE 损伤。我们的研究结果表明，在 Aβ的刺激下，RPE 介导的炎症是多靶向的，而 RelA、RelB 和 c-Rel 蛋白可能是抗炎药物的新靶点。
