通过抑制NFKB和JAK-STAT通路来向协同性内皮炎症
Stijn A Groten1, Pieter Langerhorst1, Georgios Malamas1
1Department of Molecular Hematology, Sanquin Research, Plesmanlaan 125, 1066 CX Amsterdam, the Netherlands.
iScience
|September 2, 2025
概括
针对NFKB和JAK/STAT通路可以减少血管疾病中的内皮炎症. 抑制剂阻断了TNFα和IFNγ联合刺激引起的关键炎症反应和细胞外氏因子网络.
科学领域:
- 血管生物学
- 免疫学
- 细胞生物学
背景情况:
- 系统性血管炎症包括内皮功能障碍.
- 瘤消亡因子-α (TNFα) 和干扰因子-γ (IFNγ) 通过NFKB和JAK/ STAT途径协同促进内皮细胞 (EC) 的高炎症.
研究的目的:
- 研究针对NFKB和JAK/STAT通路对EC炎症的影响.
- 了解用TNFα和IFNγ刺激的ECFCs的全系统蛋白质变化,无论是否含有途径抑制剂.
主要方法:
- 使用基于质谱的蛋白质组学来分析内皮殖民地形成细胞 (ECFC).
- 针对NFKB (IKK2 / STAT3抑制剂TPCA1) 和JAK/ STAT (JAK1抑制剂伊塔西提尼布) 途径的应用抑制剂.
- 检查了蛋白质表达的变化,包括 pyroptosis介质和化学因子,并可视化了Von Willebrand Factor (VWF) 网络.
主要成果:
- 雅克1抑制剂伊塔西替尼可选择性地阻断IFNγ诱导的蛋白质变化,而TPCA1则减弱了对TNFα和IFNγ的反应.
- 这两种抑制剂有效抑制了大多数TNFα+IFNγ诱导的蛋白质,表明这两种途径的协同作用.
- 联合刺激导致细胞外VWF网络,这被两种抑制剂逆转.
结论:
- 结合TNFα和IFNγ刺激诱导了依赖于NFKB和JAK/STAT通路的协同性内皮炎症.
- 用伊塔西尼布和TPCA1等抑制剂向这些途径可以逆转EC的关键炎症表型.
- 这项研究为开发血管疾病内皮炎症治疗策略提供了基础.
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