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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Veröffentlicht in:The EMBO journal 2000-08, Vol.19 (16), p.4292-4297
Hauptverfasser: Goh, Kee Chuan, deVeer, Michael J., Williams, Bryan R.G.
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Williams, Bryan R.G.
description 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.
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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.</abstract><cop>Chichester, UK</cop><pub>John Wiley &amp; Sons, Ltd</pub><pmid>10944112</pmid><doi>10.1093/emboj/19.16.4292</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record>
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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
title The protein kinase PKR is required for p38 MAPK activation and the innate immune response to bacterial endotoxin
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