There are four distinct receptor subtypes for adenosine, i.e. A1, A2A, A2B and A3 adenosine receptors [7
]. Adenosine receptors are G-protein coupled receptors and particularly Gs-protein-coupled A2A and A2B adenosine receptors can increase intracellular cAMP levels by activating adenylate cyclase. Expression pattern of adenosine receptor subtypes varies dependent on cell types. Pharmacological and biochemical studies established that A2AR are predominant subtype in immune cells [4
] and adenosine-A2AR interaction is capable of inhibiting inflammation by cAMP induction. The anti-inflammatory effects of extracellular adenosine through adenosine receptor signaling has been known and investigated for a long time [7
]. Others have shown that anti-inflammatory drugs, such as methotrexate, sulfasalazine and aspirin, exert their anti-inflammatory effects by triggering the accumulation of extracellular adenosine in tissues [8
]. The next question was whether the adenosine-A2AR pathway is actually involved in the regulation of activated immune cells in vivo
A2AR-deficient mice were first developed in order to study cardiovascular and neurological systems where A2ARs are widely distributed [10
]. A2AR-deficient mice quickly became a valuable research tool in immunological studies of A2AR function. We hypothesized that if the A2AR-mediated signaling is negatively regulating overactive immune cells, the intensity and duration of inflammatory responses will be increased in A2AR-deficient mice. The induction of hepatic inflammation in A2AR-deficient mice provided an evidence for the physiological immunoregulatory role of A2AR. To induce T cell-dependent acute hepatitis, we injected concanavalin A into mice at a dose creating moderate liver damage in wild-type mice. The same dose of concanavalin A in A2AR-deficient mice, however, was much more devastating compared to wild-type mice [12
]. In the same A2AR-deficient mice, concanavalin A injection resulted in sustained and elevated levels of pro-inflammatory cytokines [12
]. Augmented inflammatory response in A2AR-deficient animals was also observed in CpG oligonulceotide-activated myeloid cells, ischemia-reperfusion injury, sepsis, and toxin-induced lung inflammation [13
]. In addition to cytokines, A2AR stimulation suppresses leukocytes infiltration in response to inflammatory chemokines such as RANTES, MCP-1 and IL-8 [17
]. These studies demonstrate a crucial immunosuppressive role of A2AR in pathophysiological conditions.
A2B adenosine receptors (A2BR) are also Gs-coupled receptors which are co-expressed with A2AR in immune cells. Recent development of A2BR-selective agents and A2BR-deficient mice revealed various functions of A2BR in inflammation. Stimulation of A2BR upregulates IL-6 production, and plays a proinflammatory role in the exacerbation of allergic asthma and colitis [18
]. However, studies using gene-deficient mice showed an anti-inflammatory role of A2BR, i.e. spontaneous vascular inflammation and exacerbated lung injury in A2BR-deficient mice [21
]. Since A2BR are expressed on both immune cells and epithelial cells, these controversial results may be caused by difference in cell type-specific responses to adenosine via A2BR during inflammation.