Protein kinase R-dependent regulation of interleukin-10 in response to double-stranded RNA.
The double-stranded RNA-activated protein kinase R (PKR) is an important component of antiviral defense. PKR participates in different signaling pathways in response to various stimuli to regulate translation via phosphorylation of the eukaryotic initiation factor 2alpha, and transcription via activating NF-kappaB and IRF-1, to induce pro-inflammatory cytokines. Here we show PKR regulates interleukin-10 induction in response to double-stranded RNA, bacterial lipopolysaccaride, and Sendai virus infection. Using chemical inhibitors, dominant negative constructs, and genetic knockouts, we demonstrate that the PKR-mediated interleukin-10 induction engages JNK and NF-kappaB. Together, our data demonstrate the role of PKR in regulating an anti-inflammatory cytokine. The findings have significance in antiviral as well as broader innate immune responses.
Chakrabarti
Arindam
A
Department of Cancer Biology, Cleveland, Ohio 44195.
Sadler
Anthony J
AJ
Monash Institute of Medical Research, Monash University, Clayton, Victoria 3168, Australia.
Kar
Niladri
N
Department of Cancer Biology, Cleveland, Ohio 44195; Department of Molecular Cardiology, Lerner Research Institute, The Cleveland Clinic, Cleveland, Ohio 44195.
Young
Howard A
HA
Laboratory of Experimental Immunology, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702.
Silverman
Robert H
RH
Department of Cancer Biology, Cleveland, Ohio 44195.
Williams
Bryan R G
BRG
Monash Institute of Medical Research, Monash University, Clayton, Victoria 3168, Australia. Electronic address: bryan.williams@med.monash.edu.au.
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D012330:RNA, Double-Stranded / Q000737:chemistry*; D019892:eIF-2 Kinase / Q000378:metabolism*
D016207:Cytokines; D050856:Interferon Regulatory Factor-1; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012330:RNA, Double-Stranded; D016753:Interleukin-10; D019892:eIF-2 Kinase; D048670:MAP Kinase Kinase 4