The protein kinase PKR is required for p38 MAPK activation and the innate immune response to bacterial endotoxin

Protein kinase RNA‐regulated (PKR) is an established component of innate antiviral immunity. Recently, PKR has been shown to be essential for signal transduction in other situations of cellular stress. The relationship between PKR and the stress‐activated protein kinases (SAPKs), such as p38 mitogen...

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Bibliographic Details
Published in:	The EMBO journal Vol. 19; no. 16; pp. 4292 - 4297
Main Authors:	Goh, Kee Chuan, deVeer, Michael J., Williams, Bryan R.G.
Format:	Journal Article
Language:	English
Published:	Chichester, UK John Wiley & Sons, Ltd 15.08.2000 Nature Publishing Group UK Springer Nature B.V Oxford University Press
Subjects:	Animals Anisomycin - pharmacology Arsenites - pharmacology Bacterial Proteins - metabolism Cell Line Crosses, Genetic Cytokines - metabolism eIF-2 Kinase - metabolism eIF-2 Kinase - physiology Electrophoresis, Polyacrylamide Gel Endotoxins Endotoxins - immunology Endotoxins - pharmacology Enzyme Activation Enzyme Inhibitors - pharmacology Female Fibroblasts - immunology Fibroblasts - metabolism Genotype Hot Temperature Humans Hydrogen Peroxide - pharmacology Immune response innate immunity Interleukin-12 - metabolism Interleukin-6 - metabolism interleukins JNK Mitogen-Activated Protein Kinases lipopolysaccharides Lipopolysaccharides - metabolism LPS Male MAP Kinase Kinase 4 Mice Mice, Inbred C57BL Mice, Mutant Strains Mitogen-Activated Protein Kinase Kinases - metabolism Mitogen-Activated Protein Kinases - metabolism Models, Biological Nucleic Acid Synthesis Inhibitors - pharmacology p38 MAPK p38 Mitogen-Activated Protein Kinases PKR Reverse Transcriptase Polymerase Chain Reaction RNA, Double-Stranded - metabolism Signal Transduction Sodium Chloride - pharmacology Sodium Compounds - pharmacology Time Factors Ultraviolet Rays innate immunity p38 MAPK PKR LPS interleukins
ISSN:	0261-4189, 1460-2075, 1460-2075
Online Access:	Get full text
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Summary:	Protein kinase RNA‐regulated (PKR) is an established component of innate antiviral immunity. Recently, PKR has been shown to be essential for signal transduction in other situations of cellular stress. The relationship between PKR and the stress‐activated protein kinases (SAPKs), such as p38 mitogen‐activated protein kinase (MAPK), is not clear. Using embryonic fibroblasts from PKR wild‐type and null mice, we established a requirement for PKR in the activation of SAPKs by double‐stranded RNA, lipopolysaccharide (LPS) and proinflammatory cytokines. This does not reflect a global failure to activate SAPKs in the PKR‐null background as these kinases are activated normally by anisomycin and other physicochemical stress. Activation of p38 MAPK was restored in immortalized PKR‐null cells by reconstitution with human PKR. We also show that LPS induction of interleukin‐6 and interleukin‐12 mRNA is defective in PKR‐null cells, and that production of these cytokines is impaired in PKR‐null mice challenged with LPS. Our findings indicate, for the first time, that PKR is required for p38 MAPK signaling and plays a potentially important role in the innate response against bacterial endotoxin.
Bibliography:	ark:/67375/WNG-21X335PK-4 ArticleID:EMBJ7593246 istex:4343A227515E8D80E8CFAF85F3C9DE7DBDF2F38E ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Article-2 ObjectType-Feature-1 content type line 23 Corresponding author e-mail: williab@ccf.org
ISSN:	0261-4189 1460-2075 1460-2075
DOI:	10.1093/emboj/19.16.4292