title: Role of protein kinase R in double-stranded RNA-induced expression of nitric oxide synthase in human astroglia.
abstract: 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.
authors.affiliation: Department of Oral Biology, University of Nebraska Medical Center, Lincoln, NE 68583-0740, USA.
authors.forename: Corey J
authors.initials: CJ
authors.lastname: Auch
authors.forename: Ramendra N
authors.initials: RN
authors.lastname: Saha
authors.forename: Faruk G
authors.initials: FG
authors.lastname: Sheikh
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Liu
authors.forename: Bertram L
authors.initials: BL
authors.lastname: Jacobs
authors.forename: Kalipada
authors.initials: K
authors.lastname: Pahan
mesh_terms: 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
chemical_list: 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