通过LPS诱导TNF-alpha是通过一个Tpl2/ERK-依赖的途径进行后转录调节的
C D Dumitru1, J D Ceci, C Tsatsanis
1Kimmel Cancer Center, Department of Microbiology and Immunology, Thomas Jefferson University, 233 S. 10th Street, Philadelphia, PA 19107, USA.
Cell
|February 13, 2001
概括
Tpl2淘汰赛小鼠显示瘤亡因子-α (TNF-α) 的产生和对病理的抵抗性降低. Tpl2信号特别促进TNF-α mRNA运输,影响其诱导.
科学领域:
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
- 细胞信号传递 细胞信号传递
背景情况:
- 瘤亡因子-α (TNF-α) 是免疫反应和炎症中的关键细胞因子.
- Tpl2是一种涉及各种细胞信号通路的激酶,但其在TNF-α调节中的确切作用尚未完全理解.
研究的目的:
- 调查TPl2在脂聚糖 (LPS) 诱导的TNF-alpha产生和相关信号通路中的作用.
- 阐明TPL2影响TNF-α mRNA表达和局部化的分子机制.
主要方法:
- 使用TPL2淘汰赛小鼠和野生类型的 littermates进行比较分析.
- 用LPS刺激腹巨细胞,并评估细胞因子的产生和MAPK通路的激活.
- 采用MEK抑制剂PD98059来探测ERK1/2在TNF-α诱导中的作用.
- 研究了AU丰富元素删除在TNF-αmRNA中的影响.
- 进行亚细胞分离以追踪TNF-α mRNA局部化.
主要成果:
- Tpl2淘汰赛小鼠在暴露于LPS时表现出明显较低的TNF-alpha水平,并且对LPS/D-Galactosamine诱导的病理学有抵抗力.
- 在TPl2缺陷巨细胞中LPS刺激未能激活MEK1,ERK1和ERK2,而JNK,p38 MAPK和NF-kappaB仍然活跃.
- 在正常巨细胞中抑制MEK1/2模仿了在Tpl2淘汰赛细胞中观察到的TNF-alpha诱导缺陷.
- 改变TNF-αmRNA中富含AU的基因减少了TPl2缺乏对其诱导的影响.
- 发现TPL2信号特别增强了TNF-α mRNA的核至细胞质运输.
结论:
- Tpl2在LPS诱导的TNF-alpha产生中起着至关重要的作用,主要是通过调节MEK/ERK通路激活.
- TPL2的激酶活性对于TNF-αmRNA从细胞核到细胞质的有效运输至关重要,从而控制其翻译和诱导.
- 这些发现突出了TPL2作为通过调节TNF-α mRNA动态来调节炎症反应的关键调节者.
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