TRIF signaling stimulates translation of TNF-alpha mRNA via prolonged activation of MK2
| Autor: | Bernhard Holzmann, Christopher Tiedje, Petra Gais, Matthias Gaestel, Heike Weighardt, Felicitas Altmayr |
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| Rok vydání: | 2010 |
| Předmět: |
Time Factors
MAP Kinase Signaling System p38 mitogen-activated protein kinases Immunology Bone Marrow Cells Mice Transgenic Protein Serine-Threonine Kinases p38 Mitogen-Activated Protein Kinases Mice Protein biosynthesis Immunology and Allergy Animals Humans RNA Messenger Protein kinase A Cells Cultured Mice Knockout Chemistry Tumor Necrosis Factor-alpha Intracellular Signaling Peptides and Proteins Signal transducing adaptor protein Dendritic Cells Cell biology Mice Inbred C57BL Adaptor Proteins Vesicular Transport TRIF Protein Biosynthesis TLR4 Tumor necrosis factor alpha Signal transduction |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 184(10) |
| ISSN: | 1550-6606 |
| Popis: | 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-α biosynthesis. We provide evidence that, in LPS-stimulated murine dendritic cells, TRIF stimulates TNF-α biosynthesis selectively at the posttranscriptional level by promoting mRNA translation. In the absence of functional TRIF, the production of TNF-α protein was severely impaired, whereas TNF-α 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-α protein, but not of mRNA, in bone marrow-derived macrophages. In peritoneal macrophages, however, TRIF was also required for normal induction of TNF-α mRNA, suggesting cell type-related functions of TRIF. The influence of TRIF on dendritic cell TNF-α 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-κB. Inhibition of late p38 activity attenuated LPS-stimulated elevation of TNF-α 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-α protein production but did not affect TNF-α mRNA induction. Together, these results indicate that the TRIF signaling pathway promotes TNF-α mRNA translation through activation of the protein kinase MK2. |
| Databáze: | OpenAIRE |
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