Dexamethasone-induced expression of endothelial mitogen-activated protein kinase phosphatase-1 involves activation of the transcription factors activator protein-1 and 3′,5′-cyclic adenosine 5′-monophosphate response element-binding protein and the generation of reactive oxygen species
Dexamethasone-induced expression of endothelial mitogen-activated protein kinase phosphatase-1 involves activation of the transcription factors activator protein-1 and 3′,5′-cyclic adenosine 5′-monophosphate response element-binding protein and the generation of reactive oxygen species
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DOI：
10.1210/en.2007-1524
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发表时间：
2008-07-01
期刊：
影响因子：
4.8
通讯作者：
Vollmar, Angelika M.
中科院分区：
文献类型：
--
作者：
Fuerst, Robert;Zahler, Stefan;Vollmar, Angelika M.
我们最近发现 MAPK 磷酸酶 (MKP)-1 是人内皮细胞中糖皮质激素（地塞米松）抗炎特性的新型介质。然而，对于内皮细胞中地塞米松上调 MKP-1 的信号通路尚不清楚。了解这种新的糖皮质激素作用替代方式的分子基础可以有助于识别新的抗炎药物靶点。因此，我们研究的目的是阐明潜在的分子机制。使用蛋白质印迹分析，我们发现地塞米松快速激活人脐静脉内皮细胞中的 ERK、c-jun N 末端激酶 (JNK) 和 p38 MAPK。通过应用激酶抑制剂 PD98059（MAPK 激酶-1）和 SP600125（JNK），ERK 和 JNK 被证明对于 MKP-1 的诱导至关重要。使用EMSA和诱饵寡核苷酸方法，发现转录因子激活蛋白-1（由ERK和JNK激活）和cAMP反应元件结合蛋白（由ERK激活）参与地塞米松对MKP-1的上调。有趣的是，地塞米松诱导活性氧的产生（通过二氢荧光素测定测量），活性氧通过触发 JNK 激活参与信号传导过程。我们的工作阐明了一种新的替代机制，用于在人内皮细胞中传导糖皮质激素的抗炎作用。因此，我们的研究为寻找糖皮质激素使用的新抗炎原理的努力提供了有价值的信息。这可能有助于获得新的治疗选择，以限制糖皮质激素的副作用并克服耐药性。
We have recently identified the MAPK phosphatase (MKP)-1 as a novel mediator of the antiinflammatory properties of glucocorticoids (dexamethasone) in the human endothelium. However, nothing is as yet known about the signaling pathways responsible for the up-regulation of MKP-1 by dexamethasone in endothelial cells. Knowledge of the molecular basis of this new alternative way of glucocorticoid action could facilitate the identification of new antiinflammatory drug targets. Thus, the aim of our study was to elucidate the underlying molecular mechanisms. Using Western blot analysis, we found that dexamethasone rapidly activates ERK, c-jun N-terminal kinase (JNK), and p38 MAPK in human umbilical vein endothelial cells. By applying the kinase inhibitors PD98059 (MAPK kinase-1) and SP600125 (JNK), ERK and JNK were shown to be crucial for the induction of MKP-1. Using EMSA and a decoy oligonucleotide approach, the transcription factors activator protein-1 (activated by ERK and JNK) and cAMP response element-binding protein (activated by ERK) were found to be involved in the up-regulation of MKP-1 by dexamethasone. Interestingly, dexamethasone induces the generation of reactive oxygen species (measured by dihydrofluorescein assay), which participate in the signaling process by triggering JNK activation. Our work elucidates a novel alternative mechanism for transducing antiinflammatory effects of glucocorticoids in the human endothelium. Thus, our study adds valuable information to the efforts made to find new antiinflammatory principles utilized by glucocorticoids. This might help to gain new therapeutic options to limit glucocorticoid side effects and to overcome resistance.