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

被引:69
作者
Liu, JSH
John, GR
Sikora, A
Lee, SC
Brosnan, CF
机构
[1] Yeshiva Univ Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10461 USA
[2] Yeshiva Univ Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA
[3] Yeshiva Univ Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10461 USA
关键词
P2; receptors; IL-1; beta; TNF alpha; human fetal astrocytes; transcription factor NF-kappa B; transcription factor AP-1;
D O I
10.1523/JNEUROSCI.20-14-05292.2000
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
In human astrocytes, interleukin-1 beta (IL-1 beta) 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-1 beta-stimulated expression of nitric oxide, tumor necrosis factor (TNF alpha), and IL-6 at both the protein and mRNA levels, without affecting cell viability. In cells transiently transfected with reporter constructs, IL-1 beta demonstrated more potent activation of the transcription factors nuclear factor -kappa B (NF-kappa B) and activator protein-1 (AP-1) than TNF alpha. However, pretreatment with oATP downregulated activation of NF-kappa B and AP-1 by IL-1 beta or TNF alpha. Electromobility shift assays using oligonucleotides containing specific NF-kappa B 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-1 beta and TNF alpha 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.
引用
收藏
页码:5292 / 5299
页数:8
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