Faculty Collaboration Database

Adenosine inhibits tumor necrosis factor-alpha release from mouse peritoneal macrophages via A2A and A2B but not the A3 adenosine receptor. J Pharmacol Exp Ther 2006 Apr;317(1):172-80

Date

12/13/2005

Pubmed ID

16339914

DOI

10.1124/jpet.105.096016

Scopus ID

2-s2.0-33645115158 (requires institutional sign-in at Scopus site)   181 Citations

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-alpha (TNF-alpha). Most of the anti-inflammatory actions of adenosine have been attributed to signaling through the A(2A) adenosine receptor (A(2A)AR). Previously, however, it has been shown that the A(3)AR agonist N(6)-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide (IB-MECA) potently inhibited TNF-alpha release from macrophages obtained from A(2A)AR "knockout" (A(2A)KO) mice, suggesting that the A(3)AR may also regulate cytokine expression. Here, we confirmed that the A(2A)AR is the primary AR subtype that suppresses TNF-alpha 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(2B)AR rather than the A(3)AR mediates the non-A(2A)AR actions of adenosine since 1) the ability of IB-MECA to inhibit TNF-alpha release was not altered in macrophages isolated from A(3)KO mice, and 2) the A(2B)AR 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-alpha release from macrophages isolated from A(2A)KO mice. Although A(2B)ARs seem capable of inhibiting TNF-alpha release, the A(2A)AR plays a dominant suppressive role since MRS 1754 did not block the ability of NECA to inhibit TNF-alpha release from macrophages isolated from wild-type (WT) mice. Furthermore, the potency and efficacy of adenosine to inhibit TNF-alpha release from WT macrophages were not influenced by blocking A(2B)ARs with MRS 1754. The data indicate that adenosine suppresses TNF-alpha release from macrophages primarily via A(2A)ARs, although the A(2B)AR seems to play an underlying inhibitory role that may contribute to the anti-inflammatory actions of adenosine under select circumstances.

Author List

Kreckler LM, Wan TC, Ge ZD, Auchampach JA

Authors

John A. Auchampach PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Tina C. Wan PhD Research Scientist II in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenosine
Adenosine A2 Receptor Agonists
Adenosine A2 Receptor Antagonists
Adenosine A3 Receptor Agonists
Adenosine A3 Receptor Antagonists
Animals
In Vitro Techniques
Macrophages, Peritoneal
Mice
Mice, Inbred C57BL
Mice, Knockout
Receptor, Adenosine A2A
Receptor, Adenosine A2B
Receptor, Adenosine A3
Reverse Transcriptase Polymerase Chain Reaction
Tumor Necrosis Factor-alpha