Anti-inflammatory preconditioning by agonists of adenosine A1 receptor

Abstract

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 thropugh its A1 receptor (A1R), and inflammatory effects through A2A receptor (A2AR). Therefore, understanding of the mechanisms that govern adenosine receptor regulation may advance treatment of various inflammatory disorders. We previously reported that peak A1R expression during leukocyte recruitment, is followed by a peak in A2AR during inflammation resolution. Principal Findings: Here, we examined whether A1R activation sequentially induces A2AR expression and by this reverses inflammation. The effect of adenosine on A1R mediated A2AR expression was examined in peritoneal macrophages (PMΦ) and primary peritoneal mesothelia cells (PMC) in vitro. Induction of A2AR was inhibited by pertussis toxin (PTX) and partly dependent on A2AR stimulation. Administration of A1R agonists to healthy mice reduced A1R expression and induced A2AR production in PMC. Mice that were preconditioned with A1R agonists before E. coli inoculation exhibited decreased TNFα and IL-6 sera levels and reduced leukocytes recruitment. Preconditioning was blocked by pretreatment with A1R antagonist, as well as, or by late treatment with A2AR antagonists, and was absent in A2AR-/- mice. Conclusions: Our data suggest that preconditioning by an A1R-agonists promotes the resolution of inflammation by inducing the production of A2AR. Future implications may include early treatment during inflammatory disorders or pretreatment before anticipated high risk inflammatory events, such as invasive and organ transplantation. © 2008 Nakav et al.