The A2B adenosine receptor protects against inflammation and excessive vascular adhesion
The A2B adenosine receptor protects against inflammation and excessive vascular adhesion
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DOI：
10.1172/jci27933
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发表时间：
2006-07-01
影响因子：
15.9
通讯作者：
Ravid, Katya
中科院分区：
文献类型：
--
作者：
Yang, Dan;Zhang, Ying;Ravid, Katya
腺苷被描述为在控制炎症中发挥作用，但尚不确定其受体介导这种作用。在这里，我们产生了一个A（2B）腺苷受体敲除/报告基因敲入（A（2B）AR敲除/报告基因敲入）小鼠模型，并显示受体基因在血管系统和巨噬细胞中的表达，与年龄，性别和品系匹配的对照小鼠相比，其消融引起低度炎症。促炎性细胞因子如TNF-α的增加和随后I κ B-α的下调是观察到的这些A（2B）AR-缺失小鼠血管系统中粘附分子上调的潜在机制。有趣的是，在A（2B）AR基因敲除小鼠中，白细胞与血管系统的粘附显著增加。与对照小鼠相比，暴露于内毒素导致A（2B）AR-无效小鼠中促炎细胞因子水平增加。骨髓移植表明，骨髓（和在较小程度上血管）A（2B）AR调节这些过程。因此，我们将A（2B）AR鉴定为主要通过从造血细胞到血管系统的信号的炎症和血管粘附的新的关键调节剂，将注意力集中在作为治疗靶点的受体上。
Adenosine has been described as playing a role in the control of inflammation, but it has not been certain which of its receptors mediate this effect. Here, we generated an A(2B) adenosine receptor-knockout/reporter gene-knock-in (A(2B)AR-knockout/reporter gene-knock-in) mouse model and showed receptor gene expression in the vasculature and macrophages, the ablation of which causes low-grade inflammation compared with age-, sex-, and strain-matched control mice. Augmentation of proinflammatory cytokines, such as TNF-alpha, and a consequent downregulation of I kappa B-alpha are the underlying mechanisms for an observed upregulation of adhesion molecules in the vasculature of these A(2B)AR-null mice. Intriguingly, leukocyte adhesion to the vasculature is significantly increased in the A(2B)AR-knockout mice. Exposure to an endotoxin results in augmented proinflammatory cytokine levels in A(2B)AR-null mice compared with control mice. Bone marrow transplantations indicated that bone marrow (and to a lesser extent vascular) A(2B)ARs regulate these processes. Hence, we identify the A(2B)AR as a new critical regulator of inflammation and vascular adhesion primarily via signals from hematopoietic cells to the vasculature, focusing attention on the receptor as a therapeutic target.