Activation of the macrophage A2b adenosine receptor regulates tumor necrosis factor-alpha levels following vascular injury.
OBJECTIVE
The control of expression of tumor necrosis factor-alpha (TNF-alpha) impacts a variety of processes during a stress response. Macrophages are a major source of TNF-alpha, the level of which is known to be regulated by adenosine. Previous studies highlighted the role of the A2a adenosine receptor in this process, while the role of the A2b adenosine receptor (A2bAR) has not been clearly identified. Here, we examined the contribution of the A2bAR to TNF-alpha regulation by macrophages at baseline and under vascular stress.


METHODS
We employed a newer A2bAR-selective ligand, BAY 60-6583 in vitro and in vivo, and an A2bAR antagonist CVT-6883, as well as examined macrophages derived from control or A2bAR knockout mice.


RESULTS
We found that the expression of the A2bAR is upregulated in macrophages derived from wild-type mice subjected to arterial injury, and this receptor activity controls the level of TNF-alpha released from macrophages.


CONCLUSIONS
We identified a significant role for the A2bAR in the regulation of TNF-alpha, which would contribute to the anti-inflammatory actions of adenosine under vascular stress. This conclusion could focus attention on this receptor as a therapeutic target.
Department of Biochemistry, Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Mass., USA.
Hongjie
H
Chen
Dan
D
Yang
Shannon H
SH
Carroll
Holger K
HK
Eltzschig
Katya
K
Ravid
D000241:Adenosine / Q000378:metabolism*; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D001158:Arteries / Q000293:injuries* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D008024:Ligands; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011687:Purines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043704:Receptor, Adenosine A2B / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D015854:Up-Regulation
D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D008024:Ligands; D011687:Purines; D011720:Pyrazoles; D043704:Receptor, Adenosine A2B; D014409:Tumor Necrosis Factor-alpha; C518643:3-ethyl-1-propyl-8-(1-(3-trifluoromethylbenzyl)-1H-pyrazol-4-yl)-3,7-dihydropurine-2,6-dione; D000241:Adenosine