MAPKAP kinase 3 suppresses Ifng gene expression and attenuates NK cell cytotoxicity and Th1 CD4 T‐cell development upon influenza A virus infection
| العنوان: | MAPKAP kinase 3 suppresses Ifng gene expression and attenuates NK cell cytotoxicity and Th1 CD4 T‐cell development upon influenza A virus infection |
|---|---|
| المؤلفون: | Carolin Nordhoff, Stephan Ludwig, Viktor Wixler, Dörthe Masemann, Georg Varga, Jay H. Bream, Matthias Gaestel, Katharina Köther |
| المصدر: | The FASEB Journal. 28:4235-4246 |
| بيانات النشر: | Wiley, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Cytotoxicity, Immunologic, MAP Kinase Signaling System, p38 mitogen-activated protein kinases, Protein Serine-Threonine Kinases, Biology, Lymphocyte Activation, medicine.disease_cause, Biochemistry, Virus, Research Communications, Proinflammatory cytokine, Interferon-gamma, Mice, Orthomyxoviridae Infections, Interferon, Gene expression, Genetics, medicine, Influenza A virus, Animals, RNA, Messenger, Molecular Biology, STAT4, Intracellular Signaling Peptides and Proteins, Th1 Cells, Killer Cells, Natural, Mice, Inbred C57BL, Gene Expression Regulation, Cancer research, Signal transduction, Biotechnology, medicine.drug |
| الوصف: | MK2 and MK3 are downstream targets of p38 and ERK1/2. They control the mRNA stability of several inflammatory cytokines, including TNF-α and IL-10. Whereas MK2 is expressed ubiquitously, the expression of MK3 is restricted to muscle, liver, and heart tissues and T and NK cells. Using Mk-deficient and wild-type (WT) mice, we demonstrated an inhibitory effect of MK3, but not of MK2, on interferon (IFN)-γ expression in T and NK lymphocytes. The results provided evidence that the inhibitory effect of MK3 is based on negative feedback phosphorylation of p38 and ERK1/2, which causes decreased binding of Stat4 to the IFN-γ promoter and reduced expression of IFN-γ mRNA and protein. Consequently, all Mk3(-/-) mice challenged with the Th1-inducing influenza A virus (IAV) survived the WT LD50 virus dose. The reduced disease severity in the Mk3(-/-) mice was accompanied by a10-fold reduction in viral lung titer and an increase in the number of activated NK cells and enhanced Th1 activation of CD4 T cells. Thus, our data describe the protein kinase MK3 as a novel regulator of the innate and adaptive immune responses.-Köther, K., Nordhoff, C., Masemann, D., Varga, G., Bream, J. H., Gaestel, M., Wixler, V., Ludwig, S. MAPKAP kinase 3 suppresses Ifng gene expression and attenuates NK cell cytotoxicity and Th1 CD4 T-cell development upon influenza A virus infection. |
| تدمد: | 1530-6860 0892-6638 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ef6d36e9381ab5a240b68fb2e0192f3fTest https://doi.org/10.1096/fj.14-249599Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....ef6d36e9381ab5a240b68fb2e0192f3f |
| قاعدة البيانات: | OpenAIRE |
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They control the mRNA stability of several inflammatory cytokines, including TNF-α and IL-10. Whereas MK2 is expressed ubiquitously, the expression of MK3 is restricted to muscle, liver, and heart tissues and T and NK cells. Using Mk-deficient and wild-type (WT) mice, we demonstrated an inhibitory effect of MK3, but not of MK2, on interferon (IFN)-γ expression in T and NK lymphocytes. The results provided evidence that the inhibitory effect of MK3 is based on negative feedback phosphorylation of p38 and ERK1/2, which causes decreased binding of Stat4 to the IFN-γ promoter and reduced expression of IFN-γ mRNA and protein. Consequently, all Mk3(-/-) mice challenged with the Th1-inducing influenza A virus (IAV) survived the WT LD50 virus dose. The reduced disease severity in the Mk3(-/-) mice was accompanied by a10-fold reduction in viral lung titer and an increase in the number of activated NK cells and enhanced Th1 activation of CD4 T cells. Thus, our data describe the protein kinase MK3 as a novel regulator of the innate and adaptive immune responses.-Köther, K., Nordhoff, C., Masemann, D., Varga, G., Bream, J. H., Gaestel, M., Wixler, V., Ludwig, S. 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