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Double-stranded RNA-activated protein kinase is required for the LPS-induced activation of STAT1 inflammatory signaling in rat brain glial cells.

Authors
Lee, JH; Park, EJ; Kim, OS; Kim, HY; Joe, EH; Jou, I
Citation
Glia, 50(1):66-79, 2005
Journal Title
Glia
ISSN
0894-14911098-1136
Abstract
PKR, the double-stranded RNA (dsRNA)-activated serine/threonine kinase, has been implicated as an important component of host responses to infection and various situations of cellular stress. The involvement of PKR in signal transduction and regulation of transcription suggested to us that it may play an important role in lipopolysaccharide (LPS)-induced activation of STAT1 in rat brain immune cells. We found that LPS rapidly stimulated the phosphorylation of PKR within 5 min, followed by phosphorylation of STAT1 at 2 h in rat primary microglia and astrocyte. Using 2-aminopurine (2-AP), a pharmacological inhibitor of PKR, and PKR-specific short interfering RNA (siRNA), we demonstrated that activation of PKR was essential for LPS-induced activation of STAT1. Inhibition of PKR activity by 2-AP resulted in suppression not only of STAT1 phosphorylation, but also of nuclear factors binding activity to GAS/ISRE elements. 2-AP also significantly suppressed the downstream events of LPS-stimulated STAT1 phosphorylation, including STAT-mediated transcriptional responses and generation of nitric oxide, a hallmark of brain inflammation. Consistent with these results, transfection of PKR-specific siRNA markedly attenuated all the STAT1 dependent inflammatory signaling responses tested. We further revealed that activation of PKR by LPS led to the induction of IFN-beta through activation of NF-kappaB, triggering the phosphorylation of STAT1 in rat brain glial cells. Taken together, these findings indicate that PKR functions as an essential modulator in LPS-induced STAT inflammatory signaling events, and provides new insight into endotoxin-induced CNS diseases following infection.
MeSH terms
AnimalsAnimals, NewbornBrain/immunologyCells, CulturedDNA-Binding Proteins/metabolism*Encephalitis/immunologyEnzyme Inhibitors/pharmacologyGenes, Regulator/drug effectsGenes, Regulator/physiologyInflammation MediatorsInterferon-beta/metabolismLipopolysaccharides/pharmacologyNF-kappa B/metabolismNeuroglia/drug effectsNeuroglia/metabolism*Nitric Oxide/metabolismPhosphorylation/drug effectsRNA, Double-Stranded/geneticsRNA, Small InterferingRatsRats, Sprague-DawleySTAT1 Transcription FactorSignal Transduction/drug effectsSignal Transduction/physiology*Time FactorsTrans-Activators/metabolism*eIF-2 Kinase/antagonists & inhibitorseIF-2 Kinase/metabolism*
DOI
10.1002/glia.20156
PMID
15630703
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
Journal Papers > Research Organization > Chronic Inflammatory Disease Research Center
AJOU Authors
박, 은정김, 희영조, 은혜주, 일로
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