Sequential activation of JAKs, STATs and xanthine dehydrogenase/oxidase by hypoxia in lung microvascular endothelial cells
Sequential activation of JAKs, STATs and xanthine dehydrogenase/oxidase by hypoxia in lung microvascular endothelial cells
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DOI：
10.1016/j.biocel.2007.08.008
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发表时间：
2008-01-01
影响因子：
4
通讯作者：
Wu, Guangyu
中科院分区：
文献类型：
--
作者：
Wang, Guansong;Qian, Pin;Wu, Guangyu
黄嘌呤脱氢酶/氧化酶（XDH/XO）与内皮损伤相关的各种病理状况有关。然而，缺氧激活 XDH/XO 的分子机制仍然很大程度上未知。在本报告中，我们确定了Janus激酶（JAK）和信号转导子和转录激活子（STAT）信号通路是否参与肺微血管内皮细胞（LMVEC）原代培养物中缺氧诱导的XDH/XO激活。我们发现缺氧在 LMVEC 中以时间依赖性方式显着增加白细胞介素 6 (IL6) 的产生。缺氧还显着增强 JAK（JAK1、JAK2 和 JAK3）和 JAK 下游效应器 STAT（STAT3 和 STAT5）的磷酸化/激活。缺氧诱导的 STAT3 激活被 IL6 抗体、JAK 抑制剂 AG490 和细胞因子信号传导抑制剂 3 (SOCS3) 阻断，这意味着缺氧促进的 IL6 分泌激活了 LMVEC 中的 JAK/STAT 通路。 STAT3 的磷酸化和 DNA 结合活性也受到 p38 MAPK 抑制剂 SB203580 和磷脂酰肌醇 3-激酶抑制剂 LY294002 的抑制，表明多种信号通路参与缺氧引起的 STAT 激活。重要的是，缺氧促进了 LMVEC 中 XDH/XO 的激活，而使用 IL6 抗体、AG490 和 SOCS3 抑制 JAK-STAT 通路可显着逆转这种激活。这些数据表明，JAK、STAT 和 XDH/XO 在缺氧时依次激活。这些数据提供了第一个证据，表明 JAK-STAT 通路参与 LMVEC 中缺氧介导的 XDH/XO 激活。 (c) 2007 Elsevier Ltd. 保留所有权利。
Xanthine dehydrogenase/oxidase (XDH/XO) is associated with various pathological conditions related to the endothetial injury. However, the molecular mechanism underlying the activation of XDH/XO by hypoxia remains largely unknown. In this report, we determined whether the Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) signaling pathway is involved in hypoxia-induced activation of XDH/XO in primary cultures of lung microvascular endothelial cells (LMVEC). We found that hypoxia significantly increased interleukin 6 (IL6) production in a time-dependent manner in LMVEC. Hypoxia also markedly augmented phosphorylation/activation of JAKs (JAK1, JAK2 and JAK3) and the JAK downstream effectors STATs (STAT3 and STAT5). Hypoxia-induced activation of STAT3 was blocked by IL6 antibodies, the JAK inhibitor AG490 and the suppressor of cytokine signaling 3 (SOCS3), implying that hypoxia-promoted IL6 secretion activates the JAK/STAT pathway in LMVEC. Phosphorylation and DNA-binding activity of STAT3 were also inhibited by the p38 MAPK inhibitor SB203580 and the phosphatidylinositol 3-kinase inhibitor LY294002, suggesting that multiple signaling pathways involved in STAT activation by hypoxia. Importantly, hypoxia promoted XDH/XO activation in LMVEC, which was markedly reversed by inhibiting the JAK-STAT pathway using IL6 antibodies, AG490 and SOCS3. These data demonstrated that JAKs, STATs and XDH/XO were sequentially activated by hypoxia. These data provide the first evidence indicating that the JAK-STAT pathway is involved in hypoxia-mediated XDH/XO activation in LMVEC. (c) 2007 Elsevier Ltd. All rights reserved.