TAK1-mediated induction of nitric oxide synthase gene expression in glial cells

Narayan R. Bhat, Qin Shen, Fan Fan

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Inflammatory cell signaling leading to transcriptional activation is primarily mediated by signal transduction via mitogen-activated protein kinase (MAPK) and NFκB pathways. A common upstream kinase that signals the activation of these pathways is TGFβ-activated kinase 1 (TAK1), which itself becomes activated in response to cytokines and upon engagement of a class of cell surface receptors involved in innate immunity, that is Toll-like receptors (TLRs) by bacterial and viral pathogens. This study directly tests the role of TAK1 in the induction of inducible nitric oxide (NO) synthase (iNOS) in glial cells, which represent immune-regulatory cells of the CNS, by transient transfection assays. Transfection of C-6 glia, primary astrocytes and a rat microglial cell line with TAK1 (but not its inactive form) along with its activator protein, TAK1-binding protein 1 (TAB1) resulted in a marked stimulation of a co-transfected rat iNOS promoter-reporter construct (iNOS-Luc). TAK1-induced iNOS-Luc activity was substantially inhibited by pharmacological inhibitors of the known downstream kinases, p38 MAPK and JNK (SB203580 and SP620125), and was almost completely blocked by co-expression of a phosphorylation mutant of IκB. TAK1/TAB1 also induced the production of NO and the expression of iNOS in microglial cells in a p38 MAPK-, JNK- and NFκB-dependent manner. The results of these studies provide evidence for an important role for TAK1-mediated intracellular signaling, via p38 MAPK, JNK and NFκB, in the transcriptional activation of iNOS in glial cells.

Original languageEnglish (US)
Pages (from-to)238-247
Number of pages10
JournalJournal of Neurochemistry
Volume87
Issue number1
DOIs
StatePublished - Oct 2003
Externally publishedYes

Keywords

  • Innate immunity
  • MAP kinase cascades
  • Microglia
  • NFκB
  • Neuroinflammation
  • Signal transduction

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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