Effect of dexamethasone on interleukin‐1β‐(IL‐1β)‐induced nuclear factor‐κB (NF‐κB) and κB‐dependent transcription in epithelial cells
Effect of dexamethasone on interleukin‐1β‐(IL‐1β)‐induced nuclear factor‐κB (NF‐κB) and κB‐dependent transcription in epithelial cells
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地塞米松对白介素-1β-（IL-1β）诱导的上皮细胞核因子-κB（NF-κB）和κB依赖性转录的影响
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发表时间：
1998
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影响因子：
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通讯作者：
P. Barnes
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作者：
R. Newton;L. Hart;D. Stevens;M. Bergmann;L. Donnelly;I. Adcock;P. Barnes
炎症性肺部疾病中上皮细胞产生炎症介质可能是糖皮质激素抗炎作用的重要靶点。核因子- kappab （NF-kappaB）是炎症基因的主要激活因子，已被认为是糖皮质激素抑制的靶点。我们利用人肺ⅱ型A549和气道上皮BEAS-2B细胞研究糖皮质激素对NF-kappaB调控和kappab依赖性转录的影响。在白细胞介素-1 β (il -1 β)处理后的A549细胞中，地塞米松对I kappaB α蛋白的消失、90分钟后的重新出现以及I kappaB α mRNA的快速诱导和转录率均无影响。p65和p50/p105蛋白的表达也不受地塞米松的影响。此外，短期（1-6小时）地塞米松预处理不影响il -1 - β对NF-kappaB DNA结合和p65核定位的快速诱导。同样，地塞米松对BEAS-2B细胞il -1 β诱导的NF-kappaB没有影响（p50/p65）。在A549细胞中稳定转染kappab依赖的报告细胞导致il -1 β或phorbol酯的8-9倍激活，地塞米松抑制了30-40%。然而，在这些细胞中，il -1 β诱导的诱导型一氧化氮合酶、粒细胞-巨噬细胞集落刺激因子和环氧化酶-2 mRNA被地塞米松抑制70-90%。因此，我们得出结论，在这些上皮细胞中，糖皮质激素的抑制作用不是通过上调I kappaB α、降低p50/p65基因表达或抑制NF-kappaB DNA结合来介导的。此外，由于地塞米松对il -1 β或phorboll -酯诱导的kappab依赖性转录的最大抑制小于40%，因此单纯抑制kappab依赖性转录本身并不能解释糖皮质激素在这些细胞中观察到的全部抑制作用。
The production of inflammatory mediators by epithelial cells in inflammatory lung diseases may represent an important target for the anti-inflammatory effects of glucocorticoids. Nuclear factor-kappaB (NF-kappaB) is a major activator of inflammatory genes and has been proposed as a target for inhibition by glucocorticoids. We have used human pulmonary type-II A549 and airway epithelial BEAS-2B cells to investigate the effect of glucocorticoids on NF-kappaB regulation and kappaB-dependent transcription. In A549 cells following interleukin-1beta (IL-1beta) treatment, there was no effect of dexamethasone on the disappearance of I kappaB alpha protein, its subsequent reappearance 90-min later or the rapid induction of I kappaB alpha mRNA and transcription rate. Expression of p65 and p50/p105 proteins were also unaffected by dexamethasone. In addition, the rapid IL-1beta-induction of NF-kappaB DNA binding and p65 nuclear localisation was unaffected by short (1-6 hours) dexamethasone pre-treatments. Similarly, BEAS-2B cells showed no effect of dexamethasone on IL-1beta-induced NF-kappaB (p50/p65). Stable transfection of a kappaB-dependent reporter in A549 cells resulted in an 8-9-fold activation by IL-1beta or phorbol ester, that was repressed 30-40% by dexamethasone. However, in these cells, IL-1beta induction of inducible nitric oxide synthase, granulocyte-macrophage colony stimulating factor and cyclooxygenase-2 mRNA showed 70-90% repression by dexamethsone. We, therefore, conclude that in these epithelial cells, the repressive effects of glucocorticoids are not mediated by up-regulation of I kappaB alpha, decreased p50/p65 gene expression or inhibition of NF-kappaB DNA binding. Furthermore, since the maximal repression of IL-1beta or phorbol-ester-induced kappaB-dependent transcription by dexamethasone was less than 40%, simple inhibition of kappaB-dependent transcription cannot by itself account for the full repressive effects of glucocorticoids observed in these cells.