The Adenosine A2b Receptor: Its Role in Inflammation
The Adenosine A2b Receptor: Its Role in Inflammation
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DOI：
10.2174/187153008786848303
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发表时间：
2008-12-01
影响因子：
1.9
通讯作者：
Rees, D. A.
中科院分区：
文献类型：
--
作者：
Ham, J.;Rees, D. A.
由于缺乏高选择性高亲和力的激动剂和拮抗剂，对腺苷A2b受体作用的研究一直是谜。在过去的几年里，基于黄嘌呤或吡咯嘧啶（多杂环）结构的几种新的拮抗剂化合物被设计出来，这些化合物已被用于定位不同组织中的A2b受体并确定其功能。最近，研究人员创造了A2b受体缺失或过度表达的动物，这表明该受体具有抗炎作用。在这篇简短的综述中，我们描述了A2b受体如何影响不同组织的炎症。在垂体前叶中，A2b受体主要存在于卵泡星状细胞中，在那里它刺激IL-6和VEGF的分泌，并通过连接蛋白43影响间隙连接通讯。A2b受体还介导支气管平滑肌、肠上皮细胞、肥大细胞等多种组织中促炎细胞因子的释放。在A2b受体基因的启动子区域存在HIF-1 α结合位点，表明它与缺氧和血管生成密切相关。靶向A2b受体也可能有助于对抗自身免疫性I型糖尿病。这些发现共同表明，A2b受体在炎症中起作用；它的确切作用，无论是促炎还是抗炎，可能取决于细胞类型。然而，一些A2b受体拮抗剂正在开发用于治疗干预，这些药物要么处于临床前阶段，要么处于I期临床试验阶段，就像用于哮喘的CVT-6883一样。
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-1 alpha 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.