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Received for publication April 7, 2004.
Revised July 30, 2004.
Accepted for publication July 30, 2004.
B-DEPENDENT INFLAMMATORY RESPONSES BY CELL TYPE-SPECIFIC MECHANISMS UPON A2A ADENOSINE RECEPTOR GENE TRANSFER
Adenosine is a potent inhibitor of inflammatory processes, and the A2A adenosine receptor (A2AAR) plays a key non-redundant role as a suppresser of inflammatory responses in vivo. Here we demonstrate that increasing A2AAR gene expression suppressed multiple inflammatory responses in human umbilical vein endothelial cells (HUVECs) and rat C6 glioma cells in vitro even in the absence of added agonist. Specifically, the induction of the adhesion molecule E-selectin by either tumour necrosis factor 
(TNF) or E. coli lipopolysaccharide (LPS) was reduced by over 70% in HUVECs, while inducible nitric oxide synthase (iNOS) induction was abolished in C6 cells following exposure to interferon-
in combination with LPS and TNF, 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-
B, a key transcription factor whose proper function was essential for optimal iNOS and E-selectin induction. While NF-B 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 IB degradation by inhibiting stimulus-induced phosphorylation, while in HUVECs A2AAR expression inhibited NF-B translocation to the nucleus independently of any effect on IB degradation, suggestive of A2AAR-mediated inhibition of this signalling pathway at multiple sites.
Key words:
Adenosine, Tumor necrosis factor, cAMP, NFkappaB, Receptor binding studies, Regulation of gene expression, Leukocytes/Mast cells
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