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Extracellular nucleotides differentially regulate interleukin-1beta signaling in primary human astrocytes:
G R John1, J E Simpson, M N Woodroofe
1Departments of Pathology and Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Summary
Extracellular nucleotides like ATP modulate interleukin-1beta (IL-1beta) signaling in human astrocytes. P2 receptor activation fine-tunes inflammatory gene transcription in the central nervous system.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Interleukin-1beta (IL-1beta) activates human astrocytes, inducing proinflammatory genes via NF-kappaB and AP-1.
- Extracellular nucleotides, released during inflammation, act on P2 receptors and may regulate IL-1beta signaling.
Purpose of the Study:
- To investigate if extracellular nucleotides regulate IL-1beta-mediated signaling in human astrocytes.
- To identify the specific P2 receptor subtypes involved in this modulation.
Main Methods:
- Reporter constructs and electromobility shift assays were used to assess NF-kappaB and AP-1 activation.
- P2 receptor antagonists and selective agonists (ATP, ADP, UTP, 2'-3'-O-(4-benzoyl-benzoyl)-ATP) were employed.
- Reverse transcription-PCR and cloning identified expressed P2 receptor subtypes.
Main Results:
- ATP potentiated IL-1beta-induced NF-kappaB and AP-1 activation, and activated AP-1 alone.
- ATP modulated IL-1beta-induced IL-8 and IP-10 gene expression.
- Human astrocytes express P2Y(1), P2Y(2), P2X(7), and P2Y(4) receptors; ADP and selective P2X(7) agonists showed varied effects, while UTP was ineffective.
Conclusions:
- Different P2 receptor subtypes differentially modulate IL-1beta signaling in human astrocytes.
- P2 receptor signaling fine-tunes inflammatory gene transcription in the human central nervous system.
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