IKKβ regulates essential functions of the vascular endothelium through kinase-dependent and -independent pathways.
IKKβ regulates essential functions of the vascular endothelium through kinase-dependent and -independent pathways.
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DOI：
10.1038/ncomms1317
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发表时间：
2011
影响因子：
16.6
通讯作者：
Rosenzweig, Anthony
中科院分区：
文献类型：
--
作者：
Ashida, Noboru;SenBanerjee, Sucharita;Kodama, Shohta;Foo, Shi Yin;Coggins, Matthew;Spencer, Joel A.;Zamiri, Parisa;Shen, Dongxiao;Li, Ling;Sciuto, Tracey;Dvorak, Ann;Gerszten, Robert E.;Lin, Charles P.;Karin, Michael;Rosenzweig, Anthony
血管内皮细胞在血液和组织之间提供选择性屏障，参与伤口愈合和血管生成，并调节组织中炎性细胞的募集。核因子(NF)-κB转录因子是生存和炎症的关键调节因子，已被认为是癌症和炎症性疾病的潜在治疗靶点。在这里，我们表明，缺乏IKKβ的小鼠比产仔小，出生的频率低于预期的孟德尔频率，与营养不良和血管减少的胎盘有关。IKK是介导NF-κB激活的初级激酶。IKKβ缺失的内皮细胞表现为血管通透性增加和迁移减少。令人惊讶的是，我们发现这些缺陷是由于IKKβ对丝氨酸苏氨酸激酶AKT激活的非依赖性作用的丧失。总之，这些数据显示了IKKβ在调节内皮通透性和迁移中的重要作用，以及IKKβ和AKT信号之间意想不到的联系。IKK激酶激活核因子-κB，这种转录因子的激活形式存在于病变组织的内皮细胞中。在本研究中，我们建立了内皮细胞中缺乏IKKβ的小鼠，结果表明，内皮细胞功能缺陷既依赖于IKK激酶活性，也不依赖于IKK激酶活性。
Vascular endothelium provides a selective barrier between the blood and tissues, participates in wound healing and angiogenesis, and regulates tissue recruitment of inflammatory cells. Nuclear factor (NF)-κB transcription factors are pivotal regulators of survival and inflammation, and have been suggested as potential therapeutic targets in cancer and inflammatory diseases. Here we show that mice lacking IKKβ, the primary kinase mediating NF-κB activation, are smaller than littermates and born at less than the expected Mendelian frequency in association with hypotrophic and hypovascular placentae. IKKβ-deleted endothelium manifests increased vascular permeability and reduced migration. Surprisingly, we find that these defects result from loss of kinase-independent effects of IKKβ on activation of the serine-threonine kinase, Akt. Together, these data demonstrate essential roles for IKKβ in regulating endothelial permeability and migration, as well as an unanticipated connection between IKKβ and Akt signalling. IKK kinases activate nuclear factor-κB, and the activated form of this transcription factor is found in endothelial cells in diseased tissue. In this study, mice lacking IKKβ in the endothelium are generated, and it is shown that defects in endothelial cell function are both IKK kinase activity dependent and independent.
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