Anti-Inflammatory Preconditioning by Agonists of Adenosine A1 Receptor

Department of Clinical Biochemistry, Soroka Medical University Center and Ben-Gurion University of the Negev, Beer-Sheva, Israel.
PLoS ONE (Impact Factor: 3.23). 02/2008; 3(5):e2107. DOI: 10.1371/journal.pone.0002107
Source: PubMed


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.
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.
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.

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Available from: Gad Shaked, Jan 10, 2014
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    • "Guanosine is the ribosylated nucleoside moiety of guanine, and the increase in guanosine may explain the decrease in guanine in gill tissue of males in the 1000 ng/L treatment on day 4. M. galloprovincialis exposed to the organophosphate chlorpyrifos and to nickel also revealed increases in guanine and adenine nucleotide metabolites (Jones et al., 2008). Adenosine is thought to cause anti-inflammatory responses by activating G s g-proteins that simulate protein kinase A (PKA) activity and G q g-proteins that regulate calcium levels and activate protein kinase C (PKC), and it is thought to cause proinflammatory responses by activating G i to reduce PKA activity (Nakav et al., 2008). Guanosine also exerts important neuroprotective and neuromodulator roles in the nervous system to counteract the stimulatory activity of glutamate, and both guanosine and adenosine are thought to increase in response to trauma (Rathbone et al., 1999). "
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    • "As previously demonstrated in cell and animal models, A1R was also involved in protective effects against ischemia/reperfusion cell injury [50], [51]. Recent studies reported that A1R in lung microvascular endothelial cells participates in microvascular permeability and leukocyte transmigration [52], and in anti-inflammatory preconditioning [53]. Data from animal models also indicate the involvement of A1R in attenuation of endotoxin-induced lung injury, pulmonary edema, and alveolar destruction. "
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    • "In particular, the opposing effects of A 2A and A 1 activation are accounted for, respectively, by an elevation or reduction in intracellular cAMP [20]. Consequently, the overall effect of adenosine on inflammatory processes depends upon the relative temporal and spatial distribution of the various adenosine receptors, as well as the influence of other effectors in the inflammatory milieu [20] "
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