The adenosine a2b receptor: its role in inflammation

Investigations into the role of the adenosine A2b receptor have been enigmatic due to the lack of good selective high affinity agonists and antagonists. Over the last few years several new antagonist compounds, based either on a xanthine or pyrrolpyrimidine (polyheterocyclic) structure have been designed and these have been used to localise A2b receptors in different tissues and to determine their function. Recently, animals harbouring either a loss or an over-expression of the A2b receptor have been created and these suggest an anti-inflammatory role for the receptor. In this short review, we describe how the A2b receptor influences inflammation in different tissues. In the anterior pituitary gland the A2b receptors exist predominantly in folliculostellate cells where it stimulates secretion of IL-6 and VEGF and influences gap-junctional communication via connexin-43. The A2b receptor also mediates the release of pro-inflammatory cytokines from many tissues such as bronchial smooth muscle, intestinal epithelial cells and mast cells. The presence of a HIF-1alpha binding site in the promoter region of the A2b receptor gene shows that it is strongly implicated in hypoxia and angiogenesis. Targeting the A2b receptor may also be useful in combating autoimmune type I diabetes. These findings, together, indicate that the A2b receptor plays a role in inflammation; its precise action, whether pro- or anti-inflammatory however may be cell type dependent. Nevertheless several A2b receptor antagonists are being developed for therapeutic intervention and these are either at the preclinical stage or in phase I clinical trials as is the case for CVT-6883 for asthma.