NF-κB inhibitor targeted to activated endothelium demonstrates a critical role of endothelial NF-κB in immune-mediated diseases
NF-κB inhibitor targeted to activated endothelium demonstrates a critical role of endothelial NF-κB in immune-mediated diseases
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DOI：
10.1073/pnas.1218219110
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发表时间：
2013-10-08
影响因子：
11.1
通讯作者：
Voll, Reinhard Edmund
中科院分区：
文献类型：
--
作者：
Sehnert, Bettina;Burkhardt, Harald;Voll, Reinhard Edmund
核转录因子 kappa B (NF-kappa B) 的激活可调节与炎症疾病发病机制密切相关的炎症基因的表达。 NF-kappa B 控制粘附分子的表达，在白细胞-内皮相互作用中发挥关键作用。我们使用“潜行配体构建体”(SLC) 选择性抑制激活的内皮细胞中的 NF-kappa B，揭示了免疫介导疾病模型中内皮细胞内 NF-kappa B 激活的关键作用。重组 SLC1 由三个模块组成：(i) E-选择素靶向结构域、(ii) 假单胞菌外毒素 A 易位结构域和 (iii) 干扰 NF-κ B 激活的 NF-κ B 必需修饰物结合效应结构域。 E-选择素特异性 SLC1 通过干扰体内外内皮 I kappa B 激酶 2 活性来抑制 NF-kappa B。在小鼠实验性腹膜炎中，SLC1 的应用大大减少了炎症细胞的外渗。此外，SLC1 治疗显着改善了类风湿性关节炎小鼠模型的病程。我们的数据表明，内皮 NF-κ B 激活与关节炎的发病机制密切相关，并且可以通过 SLC 方法以细胞类型和激活阶段依赖性方式选择性抑制。此外，我们的策略适用于以细胞类型特异性方式描绘其他致病信号通路，并能够选择性地靶向不同的细胞群，以提高治疗干预的有效性和风险效益比。
Activation of the nuclear transcription factor kappa B (NF-kappa B) regulates the expression of inflammatory genes crucially involved in the pathogenesis of inflammatory diseases. NF-kappa B governs the expression of adhesion molecules that play a pivotal role in leukocyte-endothelium interactions. We uncovered the crucial role of NF-kappa B activation within endothelial cells in models of immune-mediated diseases using a "sneaking ligand construct" (SLC) selectively inhibiting NF-kappa B in the activated endothelium. The recombinant SLC1 consists of three modules: (i) an E-selectin targeting domain, (ii) a Pseudomonas exotoxin A translocation domain, and (iii) a NF-kappa B Essential Modifier-binding effector domain interfering with NF-kappa B activation. The E-selectin-specific SLC1 inhibited NF-kappa B by interfering with endothelial I kappa B kinase 2 activity in vitro and in vivo. In murine experimental peritonitis, the application of SLC1 drastically reduced the extravasation of inflammatory cells. Furthermore, SLC1 treatment significantly ameliorated the disease course in murine models of rheumatoid arthritis. Our data establish that endothelial NF-kappa B activation is critically involved in the pathogenesis of arthritis and can be selectively inhibited in a cell type- and activation stage-dependent manner by the SLC approach. Moreover, our strategy is applicable to delineating other pathogenic signaling pathways in a cell type-specific manner and enables selective targeting of distinct cell populations to improve effectiveness and risk-benefit ratios of therapeutic interventions.