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Research ArticleArticle

Specific Inhibition of Nuclear Factor-κB–Dependent Inflammatory Responses by Cell Type-Specific Mechanisms upon A2A Adenosine Receptor Gene Transfer

William A. Sands, Anthony F. Martin, Elaine W. Strong and Timothy M. Palmer
Molecular Pharmacology November 2004, 66 (5) 1147-1159; DOI: https://doi.org/10.1124/mol.104.001107
William A. Sands
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Anthony F. Martin
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Elaine W. Strong
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Timothy M. Palmer
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Abstract

Adenosine is a potent inhibitor of inflammatory processes, and the A2A adenosine receptor (A2AAR) plays a key nonredundant role as a suppresser of inflammatory responses in vivo. In this study, we demonstrate that increasing A2AAR gene expression suppressed multiple inflammatory responses in both human umbilical vein endothelial cells (HUVECs) and rat C6 glioma cells in vitro. In particular, the induction of the adhesion molecule E-selectin by either tumor necrosis factor α (TNFα) or Escherichia coli lipopolysaccharide (LPS) was reduced by more than 70% in HUVECs, whereas inducible nitric-oxide synthase (iNOS) induction was abolished in C6 cells after exposure to interferon-γ in combination with LPS and TNFα, suggesting that the receptor inhibited a common step in the induction of each of these pro-inflammatory genes. Consistent with this hypothesis, A2AAR expression inhibited the activation of NF-κB, a key transcription factor whose proper function was essential for optimal iNOS and E-selectin induction. However, although NF-κB binding to target DNA was severely compromised in both cell types, the mechanisms by which this occurred were distinct. In C6 cells, A2AAR expression blocked IκBα degradation by inhibiting stimulus-induced phosphorylation, whereas in HUVECs, A2AAR expression inhibited NF-κB translocation to the nucleus independently of any effect on IκBα degradation. Together, these observations suggest that A2AAR-mediated inhibition NF-κB activation is a critical aspect of its anti-inflammatory signaling properties and that the molecular basis of this inhibition varies in a cell type-specific manner.

  • Received April 6, 2004.
  • Accepted July 30, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 66 (5)
Molecular Pharmacology
Vol. 66, Issue 5
1 Nov 2004
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Research ArticleArticle

Specific Inhibition of Nuclear Factor-κB–Dependent Inflammatory Responses by Cell Type-Specific Mechanisms upon A2A Adenosine Receptor Gene Transfer

William A. Sands, Anthony F. Martin, Elaine W. Strong and Timothy M. Palmer
Molecular Pharmacology November 1, 2004, 66 (5) 1147-1159; DOI: https://doi.org/10.1124/mol.104.001107

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Research ArticleArticle

Specific Inhibition of Nuclear Factor-κB–Dependent Inflammatory Responses by Cell Type-Specific Mechanisms upon A2A Adenosine Receptor Gene Transfer

William A. Sands, Anthony F. Martin, Elaine W. Strong and Timothy M. Palmer
Molecular Pharmacology November 1, 2004, 66 (5) 1147-1159; DOI: https://doi.org/10.1124/mol.104.001107
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