Antiinflammatory adaptation to hypoxia through adenosine-mediated cullin-1 deneddylation
Antiinflammatory adaptation to hypoxia through adenosine-mediated cullin-1 deneddylation
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DOI：
10.1172/jci30049
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发表时间：
2007-03-01
影响因子：
15.9
通讯作者：
Colgan, Sean R.
中科院分区：
文献类型：
--
作者：
Khoury, Joseph;Ibla, Juan C.;Colgan, Sean R.
低氧预适应（HPC）是一种主要的低氧适应性途径，是一种内源性保护机制，可使细胞耐受低氧的严重挑战。我们试图定义HPC的抗炎特性.对缺氧或HPC小鼠肺组织的cDNA微阵列分析确定了一组NF-κ B调节基因，其表达被HPC减弱。使用NF-κ B荧光素酶报告基因试验的研究证实了HPC期间NF-κ B活化的显著抑制。HPC诱导的活性是可赋予的，作为从HPC处理的细胞的可溶性上清液，并且活性级分被纯化并被鉴定为腺苷（Ado）。最近的研究表明，细菌通过cullin-1（Cul-1）去内插抑制NF-κ B，我们发现了剂量依赖性的Cul-1的去内插Ado受体刺激主要介导的Ado A2 B受体亚型。此外，siRNA介导的CSN 5（C 0 P9信号体的亚基，其负责Cul-1的去eddylation）的抑制部分逆转了HPC介导的NF-κ B的抑制。在HPC的鼠模型中，Cul-1去脱氧化是明显的，并且在缺乏细胞外Ado的动物（Cd 73（-/-）小鼠）中丢失。总之，这些结果表明HPC诱导Ado的细胞外积累并通过Cul-1的去脱氧化抑制NF-κ B活性。这些结果定义了一个分子调控途径，Ado通过该途径提供了有效的炎症特性。
A major adaptive pathway for hypoxia is hypoxic preconditioning (HPC, a form of endogenous protection that renders cells tolerant to severe challenges of hypoxia. We sought to define the and inflammatory properties of HPC. cDNA microarray analysis of lung tissue from mice subjected to hypoxia or HPC identified a cluster of NF-kappa B-regulated genes whose expression is attenuated by HPC. Studies using an NF-kappa B luciferase reporter assay confirmed a significant suppression of NF-kappa B activation during HPC. HPC-elicited activity was conferrable, as a soluble supernatant from HPC-treated cells, and the active fraction was purified and identified as adenosine (Ado). Guided by recent studies demonstrating bacterial inhibition of NF-kappa B through cullin-1 (Cul-1) deneddylation, we found a dose-dependent deneddylation of Cul-1 by Ado receptor stimulation predominantly mediated by the Ado A2B receptor subtype. Further, siRNA-mediated repression of CSN5, a subunit of the COP9 signalosome responsible for deneddylation of Cul-1, partially reversed HPC-mediated inhibition of NF-KB. Cul-1 deneddylation was evident in a murine model of HPC and lost in animals lacking extracellular Ado (Cd73(-/-) mice). Taken together, these results demonstrate that HPC induces extracellular accumulation of Ado and suppresses NF-KB activity through deneddylation of Cul-1. These results define a molecular regulatory pathway by which Ado provides potent and inflammatory properties.