Hypoxia attenuates purinergic P2X receptor-induced inflammatory gene expression in brainstem microglia
| Autor: | Gordon S. Mitchell, Stéphane Vinit, Christine M. Sibigtroth, Scott A. Friedle, Jyoti J. Watters, Stephanie M.C. Smith |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Inflammation
Biology Proinflammatory cytokine 03 medical and health sciences 0302 clinical medicine BzATP Gene expression cytokine medicine Receptor Hypoxia Original Research 030304 developmental biology 0303 health sciences Microglia Purinergic receptor Hypoxia (medical) 3. Good health Cell biology P2X4 medicine.anatomical_structure P2X1 inflammation Immunology Tumor necrosis factor alpha medicine.symptom P2X7 030217 neurology & neurosurgery |
| Zdroj: | Hypoxia |
| ISSN: | 2324-1128 |
| Popis: | Stephanie MC Smith,1,2 Gordon S Mitchell,1,2 Scott A Friedle,3 Christine M Sibigtroth,1 Stéphane Vinit,1 Jyoti J Watters1–31Department of Comparative Biosciences, 2Comparative Biomedical Sciences Training Program, 3Program in Cellular and Molecular Biology, University of Wisconsin, Madison, WI, USAAbstract: Hypoxia and increased extracellular nucleotides are frequently coincident in the brainstem. Extracellular nucleotides are potent modulators of microglial inflammatory gene expression via P2X purinergic receptor activation. Although hypoxia is also known to modulate inflammatory gene expression, little is known about how hypoxia or P2X receptor activation alone affects inflammatory molecule production in brainstem microglia, nor how hypoxia and P2X receptor signaling interact when they occur together. In the study reported here, we investigated the ability of a brief episode of hypoxia (2 hours) in the presence and absence of the nonselective P2X receptor agonist 2′(3′)-O-(4-benzoylbenzoyl)adenosine-5′-triphosphate (BzATP) to promote inflammatory gene expression in brainstem microglia in adult rats. We evaluated inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNFα), and interleukin (IL)-6 messenger RNA levels in immunomagnetically isolated brainstem microglia. While iNOS and IL-6 gene expression increased with hypoxia and BzATP alone, TNFα expression was unaffected. Surprisingly, BzATP-induced inflammatory effects were lost after hypoxia, suggesting that hypoxia impairs proinflammatory P2X-receptor signaling. We also evaluated the expression of key P2X receptors activated by BzATP, namely P2X1, P2X4, and P2X7. While hypoxia did not alter their expression, BzATP upregulated P2X4 and P2X7 mRNAs; these effects were ablated in hypoxia. Although both P2X4 and P2X7 receptor expression correlated with increased microglial iNOS and IL-6 levels in microglia from normoxic rats, in hypoxia, P2X7 only correlated with IL-6, and P2X4 correlated only with iNOS. In addition, correlations between P2X7 and P2X4 were lost following hypoxia, suggesting that P2X4 and P2X7 receptor signaling differs in normoxia and hypoxia. Together, these data suggest that hypoxia suppresses P2X receptor-induced inflammatory gene expression, indicating a potentially immunosuppressive role of extracellular nucleotides in brainstem microglia following exposure to hypoxia.Keywords: P2X4, P2X7, P2X1, BzATP, inflammation, cytokine |
| Databáze: | OpenAIRE |
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