Gomez Gregorio, Sitkovsky Michail V
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10/11N311, 10 Center Dr-MSC 1892, Bethesda, MD 20892-1892, USA.
Blood. 2003 Dec 15;102(13):4472-8. doi: 10.1182/blood-2002-11-3624. Epub 2003 Aug 28.
Inosine is an endogenous nucleoside with immunosuppressive properties that is known to inhibit the accumulation of proinflammatory cytokines and protect mice from endotoxin-induced inflammation and lung tissue damage. There are no known receptors specific for inosine, but A3 adenosine receptors (A3Rs) have been shown to bind inosine, resulting in mast cell degranulation and increased vascular permeability. The present study specifically addresses the requirement for A2aR and/or A3R for the protective effect of inosine in 2 experimental in vivo models of inflammatory disease. The data show that A3R is essential for protection against ConA-induced fulminant hepatitis since only A3R-expressing mice were protected by inosine whereas wild-type and A2aR-deficient mice exhibited severe liver damage even after administration of inosine. In addition, we show in a model of LPS-induced endotoxemia that inosine protected both A2aR-/- and A3R-/- mice from inflammation, but not A2aA3R double-null mice, indicating that in this model both A2aR and A3R were used by inosine. Thus, we demonstrate that A2a and A3 adenosine receptors are differentially utilized by inosine for the down-regulation of tissue damage under different inflammatory conditions in vivo.
肌苷是一种具有免疫抑制特性的内源性核苷，已知其可抑制促炎细胞因子的积累，并保护小鼠免受内毒素诱导的炎症和肺组织损伤。目前尚无已知的肌苷特异性受体，但已证明A3腺苷受体（A3Rs）可与肌苷结合，导致肥大细胞脱颗粒并增加血管通透性。本研究专门探讨了在两种实验性体内炎症疾病模型中，A2aR和/或A3R对肌苷保护作用的必要性。数据表明，A3R对于预防刀豆蛋白A诱导的暴发性肝炎至关重要，因为只有表达A3R的小鼠受到肌苷的保护，而野生型和A2aR缺陷型小鼠即使在给予肌苷后仍表现出严重的肝损伤。此外，我们在脂多糖诱导的内毒素血症模型中表明，肌苷可保护A2aR-/-和A3R-/-小鼠免受炎症影响，但对A2aA3R双敲除小鼠无效，这表明在该模型中肌苷同时利用了A2aR和A3R。因此，我们证明了在体内不同炎症条件下，A2a和A3腺苷受体被肌苷以不同方式利用来下调组织损伤。
