Extracellular nucleotides differentially regulate interleukin-1β signaling in primary human astrocytes:: Implications for inflammatory gene expression

被引:80
作者
John, GR
Simpson, JE
Woodroofe, MN
Lee, SC
Brosnan, CF
机构
[1] Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10461 USA
[2] Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10461 USA
[3] Sheffield Hallam Univ, Div Biomed Sci, Sheffield S1 1WB, S Yorkshire, England
关键词
P2; receptors; IL-1; beta; human fetal astrocytes; transcription factors NF-kappa B and AP-1; chemokines; extracellular nucleotides;
D O I
10.1523/JNEUROSCI.21-12-04134.2001
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The cytokine interleukin-1 beta (IL-1 beta) is a potent activator of human astrocytes, inducing or modulating expression of multiple proinflammatory genes via activation of the transcription factors nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1). In this study, we examined whether IL-1 beta 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 mM) significantly potentiated IL-1 beta -mediated activation of NF-kappaB 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 beta -mediated inflammatory gene expression was supported further by the observation that ATP potentiated the IL-1 beta -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 P2Y(1), P2Y(2), and P2X(7), as well as the ATP-insensitive receptor P2Y(4). ADP, a selective agonist for P2Y(1), produced results similar to or greater than those obtained using ATP, whereas 2'-3'-O-(4-benzoylbenzoyl)- ATP, a selective agonist for P2X(7), was less effective than ATP. In contrast, UTP, a selective agonist for P2Y(2) and P2Y(4), was ineffective. These studies indicate that different P2 receptor subtypes play distinct roles in the modulation of IL-1 beta -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.
引用
收藏
页码:4134 / 4142
页数:9
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