Ligand-activation of the adenosine A2a receptors inhibits IL-12 production by human monocytes
Ligand-activation of the adenosine A2a receptors inhibits IL-12 production by human monocytes
复制标题
配体激活腺苷 A2a 受体可抑制人类单核细胞产生 IL-12
DOI：
10.4049/jimmunol.164.1.436
复制
发表时间：
2000-01-01
影响因子：
4.4
通讯作者：
Elenkov, IJ
中科院分区：
文献类型：
--
作者：
Link, AA;Kino, T;Elenkov, IJ
腺苷（ADO）具有强有力的抗炎和免疫抑制作用。在本文中，我们解决的可能性，这些影响部分介导的抑制IL-12，促炎细胞因子和主要诱导剂的Th 1反应的分泌。我们证明，5 '-N-乙基甲酰氨基腺苷（NECA），一种非特异性ADO类似物，和2-p-（2-羰乙基）苯乙氨基-5 '-N-乙基甲酰胺腺苷（CGS-21680），一种特异性A2 α受体激动剂，在离体全血和单核细胞培养物中剂量依赖性地抑制由LPS和金黄色葡萄球菌科万菌株1诱导的人IL-12的产生，然而，A1受体激动剂2-氯-N-6-环戊基腺苷和A3受体激动剂N-6-苄基-NECA和1-脱氧-1-[6-[[（3-碘苯基）甲基]氨基]-9H-嘌呤基]-N-甲基-β-D-呋喃核糖醛酰胺仅表现出弱的抑制作用。另一方面，NECA和CGS-21680剂量依赖性地增强IL-10的产生。这些药物对单核细胞IL-12和IL-10产生的不同作用意味着这些作用是由A2 a受体信号传导介导的，而不是由ADO类似物代谢物的细胞内毒性介导的。此外，CGS-21680抑制IL-12的产生独立于内源性IL-10的诱导，因为抗IL-10 Ab不能阻止其作用。（3-氯苯乙烯基）咖啡因阻止CGS-21680对IL-12产生的抑制作用，磷酸二酯酶抑制剂Ro 20-1724剂量依赖性地增强CGS-21680的抑制作用，此外，蛋白激酶A抑制剂Rp-cAMPS逆转CGS-21680的抑制作用，表明cAMP/蛋白激酶A途径参与其作用。因此，A2 a受体的配体活化同时抑制IL-12并刺激人单核细胞产生IL-10。通过这种机制，在炎症和缺血性疾病或组织损伤期间过量释放的ADO可能有助于选择性抑制Th 1应答和细胞免疫。
Adenosine (ADO) exerts potent anti-inflammatory and immunosuppressive effects. In this paper we address the possibility that these effects are partly mediated by inhibition of the secretion of IL-12, a proinflammatory cytokine and a major inducer of Th1 responses. We demonstrate that 5'-N-ethylcarboxamidoadenosine (NECA), a nonspecific ADO analogue, and 2-p-(2-carbonylethyl)phenylethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680), a specific A2a receptor agonist, dose-dependently inhibited, in whole blood ex vivo and monocyte cultures, the production of human IL-12 induced by LPS and Stapholococcus aureus Cowan strain 1, However, the Al receptor agonist 2-Chloro-N-6-cyclopentyladenosine and the A3 receptor agonists N-6-Benzyl-NECA and 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-yl]-N-methyl-beta-D-ribofuranuronamide expressed only weak inhibitory effects. On the other hand, NECA and CGS-21680 dose-dependently potentiated the production of IL-10, The differential effect of these drugs on monocyte IL-12 and IL-10 production implies that these effects are mediated by A2a receptor signaling rather than by intracellular toxicity of ADO analogue's metabolites. Moreover, CGS-21680 inhibited IL-12 production independently of endogenous IL-10 induction, because anti-IL-10 Abs failed to prevent its effect, The selective A2a antagonist 8-(3-Chlorostyryl) caffeine prevented the inhibitory effect of CGS-21680 on IL-12 production, The phosphodiesterase inhibitor Ro 20-1724 dose-dependently potentiated the inhibitory effect of CGS-21680 and, furthermore, Rp-cAMPS, a protein kinase A inhibitor, reversed the inhibitory effect of CGS-21680, implicating a cAMP/protein kinase A pathway in its action. Thus, ligand activation of A2a receptors simultaneously inhibits IL-12 and stimulates IL-10 production by human monocytes, Through this mechanism, ADO released in excess during inflammatory and ischemic conditions, or tissue injury, may contribute to selective suppression of Th1 responses and cellular immunity.