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

      Neuroscience Letters

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

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          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.

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