Department of Clinical and Experimental Medicine, University of Ferrara, Ferrara, Italy.
Br J Pharmacol. 2010 May;160(1):101-15. doi: 10.1111/j.1476-5381.2010.00667.x. Epub 2010 Mar 19.
Adenosine is an endogenous modulator, interacting with four G-protein coupled receptors (A(1), A(2A), A(2B) and A(3)) and acts as a potent inhibitor of inflammatory processes in several tissues. So far, the functional effects modulated by adenosine receptors on human synoviocytes have not been investigated in detail. We evaluated mRNA, the protein levels, the functional role of adenosine receptors and their pharmacological modulation in human synoviocytes.
mRNA, Western blotting, saturation and competition binding experiments, cyclic AMP, p38 mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-kappaB activation, tumour necrosis factor alpha (TNF-alpha) and interleukin-8 (IL-8) release were assessed in human synoviocytes isolated from patients with osteoarthritis.
mRNA and protein for A(1), A(2A), A(2B) and A(3) adenosine receptors are expressed in human synoviocytes. Standard adenosine agonists and antagonists showed affinity values in the nanomolar range and were coupled to stimulation or inhibition of adenylyl cyclase. Activation of A(2A) and A(3) adenosine receptors inhibited p38 MAPK and NF-kappaB pathways, an effect abolished by selective adenosine antagonists. A(2A) and A(3) receptor agonists decreased TNF-alpha and IL-8 production. The phosphoinositide 3-kinase or G(s) pathways were involved in the functional responses of A(3) or A(2A) adenosine receptors. Synoviocyte A(1) and A(2B) adenosine receptors were not implicated in the inflammatory process whereas stimulation of A(2A) and A(3) adenosine receptors was closely associated with a down-regulation of the inflammatory status.
These results indicate that A(2A) and A(3) adenosine receptors may represent a potential target in therapeutic modulation of joint inflammation.
腺苷是一种内源性调节剂，与四个 G 蛋白偶联受体（A(1)、A(2A)、A(2B) 和 A(3)）相互作用，作为几种组织中炎症过程的有效抑制剂。到目前为止，腺苷受体对人滑膜细胞的功能影响尚未得到详细研究。我们评估了人滑膜细胞中腺苷受体的 mRNA、蛋白水平、功能作用及其药理学调节。
采用分离自骨关节炎患者的滑膜细胞，评估其 mRNA、Western 印迹、饱和和竞争结合实验、环磷酸腺苷、p38 丝裂原活化蛋白激酶（MAPK）和核因子（NF）-κB 激活、肿瘤坏死因子-α（TNF-α）和白细胞介素-8（IL-8）释放。
人滑膜细胞中表达 A(1)、A(2A)、A(2B) 和 A(3) 腺苷受体的 mRNA 和蛋白。标准腺苷激动剂和拮抗剂具有纳摩尔级别的亲和力，并与腺苷酸环化酶的刺激或抑制偶联。A(2A)和 A(3) 腺苷受体的激活抑制了 p38 MAPK 和 NF-κB 途径，这一作用被选择性的腺苷拮抗剂所阻断。A(2A)和 A(3) 受体激动剂降低了 TNF-α和 IL-8 的产生。磷酸肌醇 3-激酶或 G(s)途径参与了 A(3)或 A(2A)腺苷受体的功能反应。滑膜细胞 A(1)和 A(2B)腺苷受体不参与炎症过程，而 A(2A)和 A(3)腺苷受体的刺激与炎症状态的下调密切相关。
这些结果表明，A(2A)和 A(3)腺苷受体可能是治疗性调节关节炎症的潜在靶点。
