TRIF Signaling Stimulates Translation of TNF-α mRNA via Prolonged Activation of MK2
TRIF Signaling Stimulates Translation of TNF-α mRNA via Prolonged Activation of MK2
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DOI：
10.4049/jimmunol.0902456
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发表时间：
2010-05-15
影响因子：
4.4
通讯作者：
Holzmann, Bernhard
中科院分区：
文献类型：
--
作者：
Gais, Petra;Tiedje, Christopher;Holzmann, Bernhard
衔接蛋白TRIF通过TLR 3和TLR 4介导信号转导，诱导I型IFN和炎性细胞因子的产生。本研究探讨TRIF信号转导控制TNF-α生物合成的机制。我们提供的证据表明，在LPS刺激的小鼠树突状细胞中，TRIF通过促进mRNA翻译在转录后水平选择性地刺激TNF-α的生物合成。在缺乏功能性TRIF的情况下，TNF-α蛋白的产生严重受损，而TNF-α mRNA水平和稳定性以及Tnfa基因的转录活性不受影响。类似地，TRIF是在骨髓源性巨噬细胞中产生LPS诱导的TNF-α蛋白而不是mRNA所必需的。然而，在腹腔巨噬细胞中，TRIF也是正常诱导TNF-α mRNA所必需的，这表明TRIF的细胞类型相关功能。TRIF对树突状细胞TNF-α产生的影响独立于I型IFN。TRIF对于LPS刺激的树突状细胞中MAPK的延长活化是必需的，但是对于NF-κ B的活化是不必要的。晚期p38活性的抑制减弱了LPS刺激的TNF-α蛋白的升高，但不是mRNA水平。p38效应激酶MK2通过TLR 4的TRIF途径直接活化。重要的是，通过TLR 3或TLR 4刺激Mk2（-/-）细胞严重损害TNF-α蛋白的产生，但不影响TNF-α mRNA的诱导。总之，这些结果表明TRIF信号通路通过激活蛋白激酶MK2促进TNF-α mRNA翻译。免疫学杂志，2010，184：5842-5848。
The adapter protein TRIF mediates signal transduction through TLR3 and TLR4, inducing production of type I IFNs and inflammatory cytokines. The present study investigates the mechanisms by which TRIF signaling controls TNF-alpha biosynthesis. We provide evidence that, in LPS-stimulated murine dendritic cells, TRIF stimulates TNF-alpha biosynthesis selectively at the post-transcriptional level by promoting mRNA translation. In the absence of functional TRIF, the production of TNF-alpha protein was severely impaired, whereas TNF-alpha mRNA levels and stability, as well as transcriptional activity of the Tnfa gene, were not affected. Similarly, TRIF was required for production of LPS-induced TNF-alpha protein, but not of mRNA, in bone marrow-derived macrophages. In peritoneal macrophages, however, TRIF was also required for normal induction of TNF-alpha mRNA, suggesting cell type-related functions of TRIF. The influence of TRIF on dendritic cell TNF-alpha production was independent of type I IFNs. TRIF was required for prolonged activation of MAPKs in LPS-stimulated dendritic cells but was dispensable for the activation of NF-kappa B. Inhibition of late p38 activity attenuated LPS-stimulated elevation of TNF-alpha protein but not mRNA levels. The p38 effector kinase MK2 was directly activated through the TRIF pathway of TLR4. Importantly, stimulation of Mk2(-/-) cells through TLR3 or TLR4 severely impaired TNF-alpha protein production but did not affect TNF-alpha mRNA induction. Together, these results indicate that the TRIF signaling pathway promotes TNF-alpha mRNA translation through activation of the protein kinase MK2. The Journal of Immunology, 2010, 184: 5842-5848.