Dysfunction of Nrf-2 in CF epithelia leads to excess intracellular H2O2 and inflammatory cytokine production.
Dysfunction of Nrf-2 in CF epithelia leads to excess intracellular H2O2 and inflammatory cytokine production.
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DOI：
10.1371/journal.pone.0003367
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发表时间：
2008
期刊：
影响因子：
3.7
通讯作者：
Ziady AG
中科院分区：
文献类型：
--
作者：
Chen J;Kinter M;Shank S;Cotton C;Kelley TJ;Ziady AG
囊性纤维化的特点是反复肺恶化，导致肺功能恶化和最终肺衰竭。气道上皮过度的炎症反应与炎症细胞因子IL-6和IL-8的过量产生有关。其发生的机制尚不完全清楚，但正常的IL-1β介导的这些细胞因子的激活是通过H2O2依赖性信号传导发生的。因此，我们推测CFTR功能障碍导致稳态H2O2调控发生改变。我们发现3种培养的CF上皮细胞模型（1种原代和2种永生化）中H2O2水平显著升高。H2O2的增加在很大程度上促进了CF上皮中IL-6和IL-8的过量产生。三种体外和两种体内模型的蛋白质组学分析显示，与匹配的正常对照组相比，CF中调节H2O2加工的抗氧化蛋白减少了2倍以上。当细胞受到刺激时，CF与正常细胞的差异表达增强；对应于H2O2介导的IL-6和IL-8的产生增加。这种氧化还原失衡的原因是CF细胞中转录因子Nrf-2的表达和活性比正常细胞减少了约70%。正常细胞中CFTR功能的抑制产生了这种表型，而在CF细胞中，n -乙酰半胱氨酸、Nrf-2激活剂硒和Nrf-2的过表达均使H2O2加工正常化，并使IL-6和IL-8降至正常水平。我们得出结论，CF上皮中Nrf-2驱动的抗氧化反应的矛盾下降导致稳态H2O2的增加，这反过来又导致促炎细胞因子IL-6和IL-8的过量产生。抗氧化剂治疗可以在不影响正常反应的情况下改善过度的细胞因子产生。
Cystic fibrosis is characterized by recurring pulmonary exacerbations that lead to the deterioration of lung function and eventual lung failure. Excessive inflammatory responses by airway epithelia have been linked to the overproduction of the inflammatory cytokine IL-6 and IL-8. The mechanism by which this occurs is not fully understood, but normal IL-1β mediated activation of the production of these cytokines occurs via H2O2 dependent signaling. Therefore, we speculated that CFTR dysfunction causes alterations in the regulation of steady state H2O2. We found significantly elevated levels of H2O2 in three cultured epithelial cell models of CF, one primary and two immortalized. Increases in H2O2 heavily contributed to the excessive IL-6 and IL-8 production in CF epithelia. Proteomic analysis of three in vitro and two in vivo models revealed a decrease in antioxidant proteins that regulate H2O2 processing, by ≥2 fold in CF vs. matched normal controls. When cells are stimulated, differential expression in CF versus normal is enhanced; corresponding to an increase in H2O2 mediated production of IL-6 and IL-8. The cause of this redox imbalance is a decrease by ∼70% in CF cells versus normal in the expression and activity of the transcription factor Nrf-2. Inhibition of CFTR function in normal cells produced this phenotype, while N-acetyl cysteine, selenium, an activator of Nrf-2, and the overexpression of Nrf-2 all normalized H2O2 processing and decreased IL-6 and IL-8 to normal levels, in CF cells. We conclude that a paradoxical decrease in Nrf-2 driven antioxidant responses in CF epithelia results in an increase in steady state H2O2, which in turn contributes to the overproduction of the pro-inflammatory cytokines IL-6 and IL-8. Treatment with antioxidants can ameliorate exaggerated cytokine production without affecting normal responses.
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DOI：
10.1152/ajplung.1999.277.1.l113
发表时间：
1999-07-01
影响因子：
4.9
作者：
Gao, L;Kim, KJ;Forman, HJ
通讯作者：
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DOI：
10.1152/ajplung.00459.2001
发表时间：
2002-09-01
影响因子：
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作者：
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作者：
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影响因子：
3.8
作者：
Li, J;Johnson, D;Johnson, J
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影响因子：
9.6
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