脂聚糖类诱导HIF-1α积累通过MAPK p38介导的mRNA稳定和德甲敏感蛋白稳定
Chloe Lockwood1, Kalbinder K Daley1, John D O'Neil1
1Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Edgbaston B15 2TT, United Kingdom.
The Journal of biological chemistry
|December 25, 2025
概括
促炎性脂多糖胺通过p38 MAPK和tristetraprolin的失活在巨细胞中激活缺氧诱导因子1-alpha (HIF-1α). 德克萨米他通过单独的葡萄皮质激素敏感途径调节HIF-1α的稳定性.
科学领域:
- 免疫学 免疫学 免疫学
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
背景情况:
- 巨细胞利用缺氧诱导因子1-alpha (HIF-1α) 在免疫反应期间获得能量和生物合成.
- 由脂多糖 (LPS) 激活非正规的HIF-1α对于巨细胞的适应至关重要.
- 现有的关于LPS对HIF-1α调节的知识是不完整的,特别是在除基化和蛋白质分解之外的信号通路方面.
研究的目的:
- 阐明调节LPS诱导的HIF-1α积累在巨细胞中的信号机制.
- 为了研究基因激活蛋白激酶p38和tristetraprolin在HIF-1α激活中的作用.
- 确定德克萨米他抑制LPS诱导的HIF-1α积累的机制.
主要方法:
- 基因和药理学方法被使用使用初级巨细胞.
- 研究了LPS诱导的HIF-1α积累对p38 MAPK的依赖性.
- 研究了tristetraprolin酸化和失活的作用.
- 测试了德克萨米他通过双重特异性酸酶1作用的假设.
主要成果:
- 在巨细胞中LPS诱导的HIF-1α积累取决于p38 MAPK.
- 这种激活是由tristetraprolin的酸化和失活介导的,它通常针对Hif1amRNA进行降解.
- 德克萨对LPS诱导的HIF-1α积累的抑制作用是独立于双特异性酸酶1的.
- 确定了两个不同的调节机制:Hif1a mRNA稳定性的p38依赖的转录后控制和HIF-1α蛋白稳定性的葡萄皮质敏感的转化后控制.
结论:
- 在巨细胞中由LPS激活HIF-1α涉及一种新的p38依赖途径,通过tristetraprolin影响Hif1amRNA的稳定性.
- 德克萨米他通过一种独特的葡萄糖皮质激素敏感机制抑制HIF-1α积累,影响蛋白质的稳定性.
- 针对这两种途径为由HIF-1α驱动的炎症性疾病提供了潜在的治疗策略.
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