Interleukin-1β orchestrates underlying inflammatory responses in microglia via Krüppel-like factor 4

Deepak K. Kaushik, Menaka C. Thounaojam, Kanhaiya L. Kumawat, Malvika Gupta, Anirban Basu

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Microglia are the resident macrophages of the CNS, which secrete several pro- and anti-inflammatory cyto-chemokines including interleukin-1β (IL-1β), in response to pathogenic stimuli. Once secreted, IL-1β binds to IL-1 receptor present on microglia and initiates the production of inflammatory cytokines in microglia. However, the detailed information regarding the molecular mechanisms of IL-1β triggered inflammatory pathways in microglia is lacking. Our studies focused on the role of Krüppel-like factor 4 (Klf4) in mediating the regulation of pro-inflammatory gene expression upon IL-1β stimulation in microglia. Our studies show that stimulation of microglia with IL-1β robustly induces Klf4 via PI3K/Akt pathway which positively regulates the production of endogenous IL-1β as well as other pro-inflammatory markers, cyclooxygenase-2, monocyte chemoattractant protein-1 and interleukin-6 (IL-6). In addition, we report that Klf4 negatively regulates the expression of inducible nitric oxide synthase, thereby playing a key role in regulating the immunomodulatory activities of microglia. IL-1β is a potent pro-inflammatory cytokine which regulates inflammation in brain via activation of microglia. In this regard, we unravelled mechanisms for IL-1β mediated regulation of downstream Cox-2, iNOS (inducible nitric oxide synthase) as well as other cyto-chemokines in microglia and have established a role for Klf4 in mediating microglial activation. We further report that Klf4 mediates the production of endogenous IL-1β in response to exogenous IL-1β stimulation. We hereby propose a novel transcription factor underlying IL-1β mediated modulation of inflammation in the CNS. IL-1β is a potent pro-inflammatory cytokine which regulates inflammation in brain via activation of microglia. In this regard, we unravelled mechanisms for IL-1β mediated regulation of downstream Cox-2, iNOS (inducible nitric oxide synthase) as well as other cyto-chemokines in microglia and have established a role for Klf4 in mediating microglial activation. We further report that Klf4 mediates the production of endogenous IL-1β in response to exogenous IL-1β stimulation. We hereby propose a novel transcription factor underlying IL-1β mediated modulation of inflammation in the CNS.

Original languageEnglish (US)
Pages (from-to)233-244
Number of pages12
JournalJournal of Neurochemistry
Volume127
Issue number2
DOIs
StatePublished - Oct 1 2013
Externally publishedYes

Keywords

  • Krüppel-like factor 4
  • brain
  • cytokines
  • iNOS
  • neuroinflammation

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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