Synergistic expression of inducible nitric oxide synthase by phorbol ester and interferon-γ is mediated through NF-κB and ERK in microglial cells

Inn O. Han, Hee S. Kim, Hyoung Chun Kim, Eun H. Joe, Won-Ki Kim

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

A proinflammatory cytokine IFN-γ stimulates microglia in the injured brain; however, signaling pathways for IFN-γ-mediated microglia activation are not well characterized. In the present study, a protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) acts in concert with IFN-γ to enhance nitric oxide (NO) production in murine microglial BV2 cells by synergistically increasing expression of inducible NO synthase (iNOS). The synergistic NO production by PMA was in part decreased by a PKC inhibitor Gö6976. PMA alone induced activation of nuclear factor-kappa B (NF-κB) and extracellular signal-regulated kinase (ERK) of mitogen-activated protein kinases (MAPKs) subtypes, whereas IFN-γ alone had little effect. PMA and IFN-γ synergistically enhanced activity of NF-κB, but not ERK. The inhibitors of NF-κB (pyrrolidine dithiocarbamate, PDTC) and ERK (1,4-diamino-2,3-dicyano-1,4 bis[2-aminophenylthio]butadiene; U0126) markedly decreased synergistic NO production in BV2 cells treated with IFN-γ and PMA in combination. We found further that co-treatment with IFN-γ and PMA synergistically induced interferon regulatory factor-1 (IRF-1), which is the major transcription factor for IFN-γ-mediated iNOS expression. The present results demonstrate the cooperative interaction of multiple signaling pathways in the induction of NO production in activated microglial cells, and suggest that the functional interplay of these pathways may be important for the onset of microglia-mediated inflammatory responses in brain.

Original languageEnglish
Pages (from-to)659-666
Number of pages8
JournalJournal of Neuroscience Research
Volume73
Issue number5
DOIs
Publication statusPublished - 2003 Sep 1
Externally publishedYes

Fingerprint

NF-kappa B
Extracellular Signal-Regulated MAP Kinases
Phorbol Esters
Nitric Oxide Synthase Type II
Interferons
Acetates
Nitric Oxide
Microglia
Protein Kinase C
Interferon Regulatory Factor-1
Mitogen-Activated Protein Kinase 3
Protein C Inhibitor
Brain
Protein Kinase Inhibitors
Mitogen-Activated Protein Kinases
Nitric Oxide Synthase
phorbol-12-myristate
Transcription Factors
Cytokines

Keywords

  • IFN-γ
  • Inflammation
  • iNOS
  • MAPK
  • NF-κB
  • PMA

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Synergistic expression of inducible nitric oxide synthase by phorbol ester and interferon-γ is mediated through NF-κB and ERK in microglial cells. / Han, Inn O.; Kim, Hee S.; Kim, Hyoung Chun; Joe, Eun H.; Kim, Won-Ki.

In: Journal of Neuroscience Research, Vol. 73, No. 5, 01.09.2003, p. 659-666.

Research output: Contribution to journalArticle

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