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INFLAMMATION AND IMMUNOPHARMACOLOGY

Adenosine Inhibits Tumor Necrosis Factor- Release from Mouse Peritoneal Macrophages via A_2A and A_2B but Not the A₃ Adenosine Receptor

Department of Pharmacology and the Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin

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- (TNF-). Most of the anti-inflammatory actions of adenosine have been attributed to signaling through the A_2A adenosine receptor (A_2AAR). Previously, however, it has been shown that the A₃AR agonist N⁶-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide (IB-MECA) potently inhibited TNF- release from macrophages obtained from A_2AAR "knockout" (A_2AKO) mice, suggesting that the A₃AR may also regulate cytokine expression. Here, we confirmed that the A_2AAR is the primary AR subtype that suppresses TNF- release from thioglycollate-elicited mouse peritoneal macrophages induced by both Toll-like receptor-dependent (TLR) and TLR-independent stimuli, but we determined that the A_2BAR rather than the A₃AR mediates the non-A_2AAR actions of adenosine since 1) the ability of IB-MECA to inhibit TNF- release was not altered in macrophages isolated from A₃KO mice, and 2) the A_2BAR 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- release from macrophages isolated from A_2AKO mice. Although A_2BARs seem capable of inhibiting TNF- release, the A_2AAR plays a dominant suppressive role since MRS 1754 did not block the ability of NECA to inhibit TNF- release from macrophages isolated from wild-type (WT) mice. Furthermore, the potency and efficacy of adenosine to inhibit TNF- release from WT macrophages were not influenced by blocking A_2BARs with MRS 1754. The data indicate that adenosine suppresses TNF- release from macrophages primarily via A_2AARs, although the A_2BAR seems to play an underlying inhibitory role that may contribute to the anti-inflammatory actions of adenosine under select circumstances.

Address correspondence to: Dr. John A. Auchampach, Department of Pharmacology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226. E-mail: jauchamp{at}mcw.edu

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