Adenosine Receptors and Mammalian Toll-Like Receptors: Synergism in Macrophages

Adenosine is known to participate in tissue protection subsequent to ischemic events. New evidence points to a role for adenosine in promoting neovascularization through a mechanism that requires interaction with the Toll-like receptor (TLR) signaling pathway. In macrophages, the adenosine receptor subtype 2A (A(2A)R) synergizes with some but not all of the Toll-like receptors, leading to increased expression of vascular endothelial growth factor (VEGF). Simultaneously, the expression of tumor necrosis factor-alpha (TNFalpha) is decreased; this phenomenon depends on the presence of AR agonists; however, the activation of transcription factor nuclear factor-kappaB (NF-kappaB) is not attenuated in the presence of A(2A)R agonists. It appears that the addition of adenosine or other A(2A)R agonists can mediate the "angiogenic switch," in macrophages, from TNFalpha protein expression to expression of components necessary for angiogenesis. Although these observations might have important implications for wound healing, it will be important to discern whether this interaction between ARs and TLRs is necessary for angiogenesis associated with tumor growth.