Adenosine Inhibits Tumor Necrosis Factor-α Release from Mouse Peritoneal Macrophages via A2A and A2B but Not the A3 Adenosine Receptor

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Abstract
Adenosine is elaborated in injured tissues where it suppresses inflammatory responses of essentially all immune cells, including production of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α). Most of the anti-inflammatory actions of adenosine have been attributed to signaling through the A2A adenosine receptor (A2AAR). Previously, however, it has been shown that the A3AR agonist N6-(3-iodobenzyl)adenosine-5′-N-methylcarboxamide (IB-MECA) potently inhibited TNF-α release from macrophages obtained from A2AAR “knockout” (A2AKO) mice, suggesting that the A3AR may also regulate cytokine expression. Here, we confirmed that the A2AAR is the primary AR subtype that suppresses TNF-α release from thioglycollate-elicited mouse peritoneal macrophages induced by both Toll-like receptor-dependent (TLR) and TLR-independent stimuli, but we determined that the A2BAR rather than the A3AR mediates the non-A2AAR actions of adenosine since 1) the ability of IB-MECA to inhibit TNF-α release was not altered in macrophages isolated from A3KO mice, and 2) the A2BAR antagonist 1,3-dipropyl-8-[4-[((4-cyanophenyl)carbamoylmethyl)oxy]phenyl]xanthine (MRS 1754) blocked the ability of the nonselective AR agonist adenosine-5′-N-ethylcarboxamide (NECA) to inhibit TNF-α release from macrophages isolated from A2AKO mice. Although A2BARs seem capable of inhibiting TNF-α release, the A2AAR plays a dominant suppressive role since MRS 1754 did not block the ability of NECA to inhibit TNF-α release from macrophages isolated from wild-type (WT) mice. Furthermore, the potency and efficacy of adenosine to inhibit TNF-α release from WT macrophages were not influenced by blocking A2BARs with MRS 1754. The data indicate that adenosine suppresses TNF-α release from macrophages primarily via A2AARs, although the A2BAR seems to play an underlying inhibitory role that may contribute to the anti-inflammatory actions of adenosine under select circumstances.

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