Endothelial inflammation inhibitor screen

[placeholder] Endothelial inflammation is an important factor in endothelial dysfunction. TNFa and IFNg induce unique inflammation state in ECs, which is synergistically amplified when both are combined. Here we propose targeted inhibition of endothelial inflammation employing an unbiased proteomics drug inhibitor screen of NFKB and JAK/STAT targets. We show STAT6 regulates the expression of a wide range of angiogenic proteins. Inhibition of with JAK1 inhibitor itacitinib nullifies the IFNg inflammation response without off target proteomic effects. IKK2/STAT3 combined inhibition inhibited both inflammation states. Interestingly, the majority of TNFa+IFNg induced proteins could be inhibited by either JAK1 or IKK2/STAT3 inhibition, reiterating the synergetic nature of this inflammation state. Finally, we show the relation of VWF with inflammation. In conclusion we employ proteomic drug screen to assess potential drug candidates to inhibit endothelial inflammation, which highlights the feasibility of targeting the endothelium and provides an interesting outlook for future studies.

[占位符] 内皮炎症（Endothelial inflammation）是引发内皮功能障碍（endothelial dysfunction）的关键致病因素。肿瘤坏死因子α（TNFα）与干扰素γ（IFNγ）可在内皮细胞（ECs）中诱导独特的炎症状态，二者联合时该炎症状态会出现协同放大效应。本研究拟通过针对核因子κB（NF-κB）与Janus激酶/信号转导与转录激活因子（JAK/STAT）通路靶点的无偏倚蛋白质组学药物抑制剂筛选，实现内皮炎症的靶向抑制。研究证实，信号转导与转录激活因子6（STAT6）可调控大量血管生成蛋白（angiogenic proteins）的表达。使用JAK1抑制剂伊他替尼（itacitinib）可完全阻断IFNγ介导的炎症应答，且未产生脱靶蛋白质组学效应。联合抑制IκB激酶2（IKK2）/信号转导与转录激活因子3（STAT3）可同时阻断两种炎症状态。值得注意的是，多数由TNFα+IFNγ诱导的蛋白可通过JAK1抑制或IKK2/STAT3联合抑制实现阻断，进一步印证了该炎症状态的协同特性。最后，本研究揭示了血管性血友病因子（Von Willebrand factor, VWF）与炎症的关联。综上，本研究通过蛋白质组学药物筛选（proteomic drug screen）评估了潜在的内皮炎症抑制候选药物，证实了靶向干预内皮的可行性，为后续相关研究提供了颇具价值的研究展望。