Modulation of interleukin-1β and tumor necrosis factor α signaling by P2 purinergic receptors in human fetal astrocytes

Judy S.H. Liu, Gareth R. John, Andrew Sikora, Sunhee C. Lee, Celia F. Brosnan

Research output: Contribution to journalArticle

73 Scopus citations

Abstract

In human astrocytes, interleukin-1β (IL-1β) is a potent inducer of genes associated with inflammation. In this study, we tested the hypothesis that in primary cultures of human fetal astrocytes signaling by the P2 purinergic nucleotide receptor pathway contributes to, or modulates, cytokine-mediated signal transduction. Calcium imaging studies indicated that most cells in culture responded to ATP, whereas only a subpopulation responded to UTP. Pretreatment of astrocytes with P2 receptor antagonists, including suramin and periodate oxidized ATP (oATP), resulted in a significant downregulation of IL-1β-stimulated expression of nitric oxide, tumor necrosis factor (TNFα), and IL-6 at both the protein and mRNA levels, without affecting cell viability. In cells transiently transfected with reporter constructs, IL-1β demonstrated more potent activation of the transcription factors nuclear factor -κB (NF-κB) and activator protein-1 (AP-1) than TNFα. However, pretreatment with oATP downregulated activation of NF-κB and AP-1 by IL-1β or TNFα. Electromobility shift assays using oligonucleotides containing specific NF-κB binding sequences confirmed that pretreatment with oATP or apyrase attenuated cytokine-mediated induction of this transcription factor. From these data, we conclude that P2 receptor- mediated signaling intersects with that of IL-1β and TNFα to regulate responses to cytokines in the CNS. Because inflammation, trauma, and stress all lead to the release of high levels of extracellular nucleotides, such as ATP and UTP, signaling via P2 receptors may provide a mechanism whereby cells can sense and respond to events occurring in the extracellular environment and can fine tune the transcription of genes involved in the inflammatory response.

Original languageEnglish (US)
Pages (from-to)5292-5299
Number of pages8
JournalJournal of Neuroscience
Volume20
Issue number14
DOIs
StatePublished - Jul 15 2000

Keywords

  • Human fetal astrocytes
  • IL-1β
  • P2 receptors
  • TNFα
  • Transcription factor AP-1
  • Transcription factor NF-κB

ASJC Scopus subject areas

  • Neuroscience(all)

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