Role of protein kinase R in double-stranded RNA-induced expression of nitric oxide synthase in human astroglia.
Environmental factor(s), such as viral infection, has been implicated as one of the triggering events leading to neuroinflammation in multiple sclerosis. This study underlines the importance of double-stranded RNA (dsRNA), the active component of a viral infection, in inducing the expression of inducible nitric oxide synthase (iNOS) in human astroglia. DsRNA in the form of synthetic polyinosinic-polycytidylic acid (poly IC) induced expression of iNOS and iNOS promoter-driven luciferase activity through activation of nuclear factor (NF)-kappaB and CCAAT/enhancer-binding proteinbeta (C/EBPbeta). In addition, we show that inhibitors of protein kinase R attenuated iNOS by suppressing the activation of NF-kappaB but not C/EBPbeta. In contrast, knock down of p38 mitogen-activated protein kinase (MAPK) attenuated iNOS by suppressing the activation of C/EBPbeta but not NF-kappaB. This study delineates a novel role of dsRNA in inducing the expression of iNOS through dsRNA-activated protein kinase (PKR)-mediated activation of NF-kappaB and p38-mediated activation of C/EBPbeta in human astroglia that may participate in virus-induced neurological abnormalities.
Auch
Corey J
CJ
Department of Oral Biology, University of Nebraska Medical Center, Lincoln, NE 68583-0740, USA.
Saha
Ramendra N
RN
Sheikh
Faruk G
FG
Liu
Xiaojuan
X
Jacobs
Bertram L
BL
Pahan
Kalipada
K
D001253:Astrocytes / Q000201:enzymology*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D004789:Enzyme Activation; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D011070:Poly I-C / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D012330:RNA, Double-Stranded / Q000378:metabolism*; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection; D019892:eIF-2 Kinase / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D022782:CCAAT-Enhancer-Binding Protein-beta; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D012330:RNA, Double-Stranded; D008156:Luciferases; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D019892:eIF-2 Kinase; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D011070:Poly I-C