Regulation of the hypoxia-inducible factor 1α by the inflammatory mediators nitric oxide and tumor necrosis factor-α in contrast to desferroxamine and phenylarsine oxide
Regulation of the hypoxia-inducible factor 1α by the inflammatory mediators nitric oxide and tumor necrosis factor-α in contrast to desferroxamine and phenylarsine oxide
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DOI：
10.1074/jbc.m107689200
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发表时间：
2001-10-26
影响因子：
4.8
通讯作者：
Brüne, B
中科院分区：
文献类型：
--
作者：
Sandau, KB;Zhou, J;Brüne, B
缺氧/缺血状况引起缺氧诱导因子-1（HIF-1）的活化，其作为转录因子发挥作用。HIF-1由HIF-1 α和HIF-1 β亚基组成，稳定性调节通过HIF-1 α的积累/降解发生，其概念是脯氨酰羟化酶引起蛋白质水平的变化。此外，有证据表明，HIF-1是上调不同的激动剂在常氧。我们研究了炎症介质一氧化氮（NO）和肿瘤坏死因子-α（TNF-α）对HIF-1 α调节的影响。为了比较，LLC-PK 1细胞暴露于缺氧，用去铁胺（DFX，已知模拟缺氧）和硫醇交联剂氧化苯胂（PAO）刺激。虽然所有刺激引起HIF-1 α稳定与时间依赖性的积累模式的差异，显着的变化出现在信号方面。通过使用超氧阴离子（O-2（-））发生器，我们建立了一个O-2（-）敏感的通路，该通路阻断了HIF-1 α对NO和TNF-α的稳定反应，而DFX和PAO诱导的HIF-1 α稳定反应似乎对O-2（-）不敏感。NO和TNF-α信号传导需要磷酸化事件，特别是磷脂酰肌醇3-激酶/Akt的活化，这与DFX和PAO相反。基于HIF-1依赖的荧光素酶报告基因分析，发现与NO和TNF-α相反，PAO类似于诱导功能失调的HIF-1复合物的刺激。这些数据表明，不同的激动剂激活HIF-1 α在常氧条件下，通过采用不同的信号转导途径。
Hypoxic/ischemic conditions provoke activation of the hypoxia-inducible factor-1 (HIF-1), which functions as a transcription factor. HIF-1 is composed of the HIF-1 alpha and -beta subunits, and stability regulation occurs via accumulation/degradation of HIF-1 a with the notion that a prolyl hydroxylase accounts for changes in protein level. In addition, there is evidence that HIF-1 is up-regulated by diverse agonists during normoxia. We investigated the impact of inflammatory mediators nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) on HIF-1 alpha regulation. For comparison, LLC-PK1 cells were exposed to hypoxia, stimulated with desferroxamine (DFX, known to mimic hypoxia), and the thiol-crosslinking agent phenylarsine oxide (PAO). Although all stimuli elicited HIF-1 alpha stabilization with differences in the time-dependent accumulation pattern, significant variations appeared with regard to signaling. With the use of a superoxide anion (O-2(-)) generator, we established an O-2(-)-sensitive pathway that blocked HIF-1 alpha stabilization in response to NO and TNF-alpha while DFX- and PAO-evoked HIF-1 alpha stabilization appeared O-2(-)-insensitive. NO and TNF-alpha signaling required phosphorylation events, especially activation of the phosphatidylinositol 3-kinase/Akt, which is in contrast to DFX and PAO. Based on HIF-1-dependent luciferase reporter gene analysis, it was found that, in contrast to NO and TNF-alpha, PAO resembled a stimulus that induced a dysfunctional HIF-1 complex. These data indicate that diverse agonists activate HIF-1 a under normoxic conditions by employing different signaling pathways.