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Background  Adenosine levels rise during inflammation and modulate inflammatory responses by engaging with four different G protein-coupled receptors. It is suggested that adenosine exhibits pro-inflammatory effects through its A 1  receptor (A 1 R), and anti-inflammatory effects through A 2A  receptor (A 2A R). Therefore, understanding of the mechanisms that govern adenosine receptor regulation may advance treatment of various inflammatory disorders. We previously reported that peak A 1 R expression during leukocyte recruitment, is followed by a peak in A 2A R during inflammation resolution.    Principal Findings  Here, we examined whether A 1 R activation sequentially induces A 2A R expression and by this reverses inflammation. The effect of adenosine on A 1 R mediated A 2A R expression was examined in peritoneal macrophages (PMΦ) and primary peritoneal mesothelial cells (PMC)  in vitro . Induction of A 2A R was inhibited by pertussis toxin (PTX) and partly dependent on A 2A R stimulation. Administration of A 1 R agonists to healthy mice reduced A 1 R expression and induced A 2A R production in PMC. Mice that were preconditioned with A 1 R agonists 24 hours before  E. coli  inoculation exhibited decreased TNFα and IL-6 sera levels and reduced leukocytes recruitment. Preconditioning was blocked by pretreatment with A 1 R antagonist, as well as, or by late treatment with A 2A R antagonist, and was absent in A 2A R −/−  mice.    Conclusions  Our data suggest that preconditioning by an A 1 R-agonist promotes the resolution of inflammation by inducing the production of A 2A R. Future implications may include early treatment during inflammatory disorders or pretreatment before anticipated high risk inflammatory events, such as invasive surgery and organ transplantation.

Anti-Inflammatory Preconditioning by Agonists of Adenosine A1 Receptor