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The Journal of Neuroscience, June 15, 2001, 21(12):4134-4142
Extracellular Nucleotides Differentially Regulate
Interleukin-1 Signaling in Primary Human Astrocytes: Implications
for Inflammatory Gene Expression
Gareth R.
John1,
Julie
E.
Simpson3,
M. Nicola
Woodroofe3,
Sunhee C.
Lee1, and
Celia F.
Brosnan1, 2
Departments of 1 Pathology and
2 Neuroscience, Albert Einstein College of Medicine, Bronx,
New York 10461, and 3 Division of Biomedical Sciences,
Sheffield Hallam University, Sheffield, South Yorkshire S1 1WB, United
Kingdom
The cytokine interleukin-1 (IL-1) is a potent activator of
human astrocytes, inducing or modulating expression of multiple proinflammatory genes via activation of the transcription factors nuclear factor- B (NF-B) and activator protein-1 (AP-1). In this study, we examined whether IL-1 signaling is regulated in these cells by extracellular nucleotides that are released at high
concentrations under inflammatory conditions and act as ligands for
members of the P2 receptor family. Using reporter constructs and
electromobility shift assays, we found that cotreatment of astrocyte
cultures with ATP (1-100 µM) significantly potentiated
IL-1-mediated activation of NF-B and AP-1 and that ATP alone
activated AP-1. These effects were blocked by the P2 receptor
antagonists XAMR 0721, periodate-oxidized ATP, and suramin. A role for
ATP in modulating IL-1-mediated inflammatory gene expression was
supported further by the observation that ATP potentiated the
IL-1-induced expression of IL-8 mRNA and protein but strongly
downregulated IP-10 expression. Reverse transcription-PCR and
cloning demonstrated expression of the ATP-responsive P2 receptor
subtypes P2Y1, P2Y2, and
P2X7, as well as the ATP-insensitive receptor
P2Y4. ADP, a selective agonist for P2Y1,
produced results similar to or greater than those obtained using ATP,
whereas 2'-3'-O-(4-benzoyl-benzoyl)-ATP, a selective agonist for
P2X7, was less effective than ATP. In contrast, UTP,
a selective agonist for P2Y2 and P2Y4,
was ineffective. These studies indicate that different P2 receptor
subtypes play distinct roles in the modulation of IL-1-mediated
signal transduction in human astrocytes, and that signaling via P2
receptors may fine-tune the transcription of genes involved in
inflammatory responses in the human CNS.
Key words:
P2 receptors; IL-1; human fetal astrocytes; transcription factors NF-B and AP-1; chemokines; extracellular
nucleotides
Copyright © 2001 Society for Neuroscience 0270-6474/01/21124134-09$05.00/0
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