Adenosine inhibits tumor necrosis factor-α release from mouse peritoneal macrophages via A2A and A2B but not the A 3 adenosine receptor

Laura M. Kreckler, Tina C. Wan, Zhi-Dong Ge, John A. Auchampach*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

147 Scopus citations


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 N 6-(3-iodobenzyl)adenosine-5′-N-methylcarboxamide (IB-MECA) potently inhibited TNF-α release from macrophages obtained from A 2AAR "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 A 3KO 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 A 2AKO 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.

Original languageEnglish (US)
Pages (from-to)172-180
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
StatePublished - Apr 2006

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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