Glycogen synthase kinase-3 promotes the synergistic action of interferon-γ on lipopolysaccharide-induced IL-6 production in RAW264.7 cells

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Macrophages are the major effector cells of the innate immune system. Their function requires the integration of signals from pathogens, such as those induced by lipopolysaccharide (LPS), and from the host, such as those induced by interferon-γ (IFN-γ). The priming by IFN-γ of Toll-like receptor-induced macrophage activation has long been recognized, but the mechanisms underlying this priming action remain unclear. We report in this study that the priming of macrophage-derived RAW264.7 cells by IFN-γ is highly dependent on glycogen synthase kinase-3 (GSK3). Cooperative interactions of GSK3 and signal transducer and activator of transcription-3 (STAT3) were revealed by the findings that GSK3 inhibitors, or knockdown of the GSK3 β isoform, strongly reduced the activation of STAT3, but not STAT1, induced by IFN-γ without affecting upstream signaling events, and GSK3 was associated with STAT3. Direct inhibition of STAT3 activation abolished the synergistic action of IL-6 production by IFN-γ administered with LPS. Similarly, inhibition of GSK3 abolished the synergistic stimulation of IFN-γ on IL-6 production, and GSK3 was recruited to the IFN-γ receptor by co-treatment with IFN-γ and LPS. These results demonstrate the dependency of macrophage priming by IFN-γ on STAT3 and GSK3, providing novel targets for intervention.

Original languageEnglish (US)
Pages (from-to)978-985
Number of pages8
JournalCellular Signalling
Volume21
Issue number6
DOIs
StatePublished - Jun 1 2009
Externally publishedYes

Keywords

  • Cytokines
  • GSK-3
  • Inflammation
  • Lipopolysaccharide
  • Macrophage
  • Signal transduction

ASJC Scopus subject areas

  • Cell Biology

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