Suppression of inflammatory and immune responses by the A(2A) adenosine receptor: an introduction

Abstract

The purine nucleoside adenosine has been described as a 'retaliatory metabolite' by virtue of its ability to function in an autocrine manner to modify the activity of a range of cell types following its extracellular accumulation during cell stress or injury. These effects are largely protective and are triggered by the binding of adenosine to any of four G-protein-coupled adenosine receptors. Most of the anti-inflammatory effects of adenosine have been assigned to the adenosine A(2A) receptor subtype, which is expressed in many immune and inflammatory cells. In this brief article, we will outline the growing evidence to support the hypothesis that the development of agonists selective for the A(2A) receptor is an effective strategy for suppressing the exaggerated inflammatory responses associated with many diseases by virtue of the receptor's ability to inhibit multiple pro-inflammatory signalling cascades.

Figure 1

A_2A receptor-mediated inhibition of cytokine receptor activation of the JAK-STAT pathway. Binding of adenosine or synthetic agonists to the A_2A receptor triggers the activation of the stimulatory heterotrimeric G-protein G_s, which in turn activates adenylyl cyclase. The resulting elevation of cAMP levels is sensed by multiple intracellular cAMP-binding effectors, including Epac1. Epac1 functions as a cAMP-activated guanine nucleotide exchange factor for the Rap family of Ras-related small G-proteins, promoting the formation of GTP-bound Rap1a. This initiates transcription of the SOCS-3 gene via a transcription factor (TF) that has yet to be identified. In vascular endothelial cells, SOCS-3 inhibits JAK-mediated tyrosine phosphorylation of STATs after binding to tyrosine-phosphorylated Ob-Rb and gp130 following their activation by leptin and soluble IL-6 receptor α/IL-6 (sIL-6Rα/IL-6) trans-signalling complexes, respectively.