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High-throughput Quantitative Real-time RT-PCR Assay for Determining Expression Profiles of Types I and III Interferon Subtypes
Published on: March 24, 2015
MAP kinase p38α regulates type III interferon (IFN-λ1) gene expression in human monocyte-derived dendritic cells in
Miao Jiang1, Pamela Österlund2, Riku Fagerlund2
1*Virology Unit, Department of Infectious Disease Surveillance and Control, National Institute for Health and Welfare, Helsinki, Finland; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA; Department of Microbiology, Immunology, and Molecular Genetics, Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, California, USA; Institute of Biotechnology and Department of Biosciences, University of Helsinki, Finland; and Department of Virology, University of Turku, Finland miao.jiang@helsinki.fi miao.jiang@thl.fi ilkka.julkunen@thl.fi ilkka.julkunen@utu.fi.
Abstract:
Recognition of viral nucleic acids leads to type I and type III IFN gene expression and activation of host antiviral responses. At present, type III IFN genes are the least well-characterized IFN types. Here, we demonstrate that the p38 MAPK signaling pathway is involved in regulating IFN-λ1 gene expression in response to various types of RNA molecules in human moDCs. Inhibition of p38 MAPK strongly reduced IFN gene expression, and overexpression of p38α MAPK enhanced IFN-λ1 gene expression in RNA-stimulated moDCs. The regulation of IFN gene expression by p38 MAPK signaling was independent of protein synthesis and thus, a direct result of RNA stimulation. Moreover, the RIG-I/MDA5-MAVS-IRF3 pathway was required for p38α MAPK to up-regulate IFN-λ1 promoter activation, whereas the MyD88-IRF7 pathway was not needed, and the regulation was not involved directly in IRF7-dependent IFN-α1 gene expression. The stimulatory effect of p38α MAPK on IFN-λ1 mRNA expression in human moDCs did not take place directly via the activating TBK1/IKKε complex, but rather, it occurred through some other parallel pathways. Furthermore, mutations in ISRE and NF-κB binding sites in the promoter region of the IFN-λ1 gene led to a significant reduction in p38α MAPK-mediated IFN responses after RNA stimulation. Altogether, our data suggest that the p38α MAPK pathway is linked with RLR signaling pathways and regulates the expression of early IFN genes after RNA stimulation cooperatively with IRF3 and NF-κB to induce antiviral responses further.
Insights
The p38 mitogen-activated protein kinase (MAPK) pathway directly regulates type III interferon-lambda1 (IFN-λ1) gene expression in response to RNA stimulation in human dendritic cells, crucial for antiviral defense.
Area of Science:
- Immunology
- Molecular Biology
- Virology
Background:
- Type I and type III interferons (IFNs) are critical for antiviral responses.
- Type III IFNs, including IFN-λ, are less understood compared to Type I IFNs.
- Recognition of viral nucleic acids triggers IFN gene expression.
Purpose of the Study:
- To investigate the role of the p38 MAPK signaling pathway in regulating type III IFN-λ1 gene expression.
- To elucidate the molecular mechanisms by which p38 MAPK influences IFN-λ1 expression upon RNA stimulation.
Main Methods:
- Utilized human monocyte-derived dendritic cells (moDCs).
- Employed p38 MAPK inhibition and overexpression techniques.
- Investigated signaling pathways including RIG-I/MDA5-MAVS-IRF3, MyD88-IRF7, and TBK1/IKKε.
- Analyzed promoter activity using ISRE and NF-κB binding site mutations.
Main Results:
- p38 MAPK signaling is essential for RNA-induced IFN-λ1 gene expression in moDCs.
- Overexpression of p38α MAPK enhanced IFN-λ1 expression, while inhibition reduced it.
- The RIG-I/MDA5-MAVS-IRF3 pathway, but not MyD88-IRF7, was required for p38α MAPK-mediated IFN-λ1 promoter activation.
- p38α MAPK acted independently of protein synthesis and TBK1/IKKε, involving IRF3 and NF-κB.
Conclusions:
- The p38 MAPK pathway is a key regulator of early type III IFN gene expression following viral RNA detection.
- p38 MAPK cooperates with IRF3 and NF-κB to enhance IFN-λ1 expression and bolster antiviral immunity.
- Findings reveal a novel link between p38 MAPK and RNA sensing pathways in innate immunity.
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