Role of protein kinase R in double-stranded RNA-induced expression of nitric oxide synthase in human astroglia

FEBS Lett. 2004 Apr 9;563(1-3):223-8. doi: 10.1016/S0014-5793(04)00302-3.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Astrocytes / enzymology*
  • CCAAT-Enhancer-Binding Protein-beta / metabolism
  • Cell Line
  • Cells, Cultured
  • Enzyme Activation
  • Enzyme Induction / drug effects
  • Enzyme Inhibitors / pharmacology
  • Genes, Reporter
  • Humans
  • Luciferases / genetics
  • Luciferases / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-kappa B / metabolism
  • Nitric Oxide Synthase / metabolism*
  • Nitric Oxide Synthase Type II
  • Poly I-C / pharmacology
  • Promoter Regions, Genetic
  • RNA, Double-Stranded / metabolism*
  • Time Factors
  • Transcriptional Activation
  • Transfection
  • eIF-2 Kinase / metabolism*
  • p38 Mitogen-Activated Protein Kinases


  • CCAAT-Enhancer-Binding Protein-beta
  • Enzyme Inhibitors
  • NF-kappa B
  • RNA, Double-Stranded
  • Luciferases
  • NOS2 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • eIF-2 Kinase
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Poly I-C