c-Jun N-terminal kinase and p38 mitogen-activated protein kinase mediate double-strand RNA-induced inducible nitric oxide synthase expression in microglial cells

Neurosci Lett. 2008 Mar 15;433(3):215-8. doi: 10.1016/j.neulet.2007.10.052. Epub 2008 Jan 16.


Double-stranded RNA (dsRNA) has been implicated as a potential immune stimulant in activating microglia, which can cause chronic neurodegeneration. In this study, we examined the involvement of different types of mitogen-activated protein kinases (MAPKs) in the induction of inducible nitric oxide synthase (iNOS) by dsRNA in microglial cells. Nitric oxide production was increased after exposure of microglia to 50mug/mL dsRNA. Levels of dsRNA-induced nitrite production in a line of immortalized murine microglia (BV2) and in primary cultures of murine microglia were decreased by inhibition of JNK or p38 MAPK, but were increased by inhibition of extracellular signal-regulated kinase. Similar results were shown in the levels of dsRNA-induced iNOS gene expression in BV2 cells. Phosphorylation levels of p38 MAPK were increased, depending on p38 MAPK inhibitor concentrations, while activation levels of MAPKAPK2, a known p38 substrate, were inhibited. Thus, it is likely that SB203580 inhibited the kinase activity of p38 MAPK, resulting in the loss of a feedback inhibition regulatory loop of p38 MAPK in BV2 cells. These findings suggest that dsRNA stimulated iNOS expression via MAPK signaling pathways, including JNK and p38 MAPK.

MeSH terms

  • Animals
  • Cell Line, Transformed
  • Enzyme Inhibitors / pharmacology
  • Feedback, Physiological / drug effects
  • Feedback, Physiological / physiology
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / genetics
  • Gliosis / enzymology*
  • Gliosis / genetics
  • Gliosis / physiopathology
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / genetics
  • Mice
  • Microglia / drug effects
  • Microglia / enzymology*
  • Nitric Oxide / biosynthesis
  • Nitric Oxide Synthase Type II / metabolism*
  • Phosphorylation / drug effects
  • RNA, Double-Stranded / genetics
  • RNA, Double-Stranded / metabolism*
  • RNA, Double-Stranded / pharmacology
  • Up-Regulation / drug effects
  • Up-Regulation / genetics
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Enzyme Inhibitors
  • RNA, Double-Stranded
  • Nitric Oxide
  • Nitric Oxide Synthase Type II
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases