Anti-inflammatory preconditioning by agonists of adenosine A1 receptor.
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.


RESULTS
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 (PMPhi) 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 TNFalpha 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.
Nakav
Sigal
S
Department of Clinical Biochemistry, Soroka Medical University Center and Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Chaimovitz
Cidio
C
Sufaro
Yuval
Y
Lewis
Eli C
EC
Shaked
Gad
G
Czeiger
David
D
Zlotnik
Moshe
M
Douvdevani
Amos
A
D000241:Adenosine / Q000378:metabolism; D058907:Adenosine A1 Receptor Agonists; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D004848:Epithelium / Q000502:physiology; D005260:Female; D007249:Inflammation / Q000235:genetics / Q000503:physiopathology; D019194:Ischemic Preconditioning; D051379:Mice; D018345:Mice, Knockout; D010538:Peritonitis / Q000503:physiopathology; D037342:Pertussis Toxin / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000502:physiology
D058907:Adenosine A1 Receptor Agonists; D000893:Anti-Inflammatory Agents; D043705:Receptor, Adenosine A2A; D037342:Pertussis Toxin; D000241:Adenosine