Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation of MKP-1
Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation of MKP-1
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DOI：
10.1093/emboj/20.24.7108
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发表时间：
2001-12-17
期刊：
影响因子：
11.4
通讯作者：
Cato, ACB
中科院分区：
文献类型：
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作者：
Kassel, O;Sancono, A;Cato, ACB
糖皮质激素抑制转录因子如AP-1和NF-κ B以及各种细胞信号分子的促炎活性。这些信号分子之一是细胞外信号调节激酶（Erk-1/2），其控制过敏介质的释放和肥大细胞中促炎细胞因子基因表达的诱导。糖皮质激素抑制Erk-1/2活性的机制尚不清楚。在这里，我们报告了一种新的糖皮质激素的双重作用，这种抑制。糖皮质激素在启动子水平增加MAP激酶磷酸酶-1（MKP-1）基因的表达，并减弱MKP-1的蛋白酶体降解，我们报告这是由肥大细胞激活引发的。MKP-1表达的诱导和其降解的抑制对于糖皮质激素介导的Erk-1/2活化的抑制是必需的。在NIH-3 T3成纤维细胞中，尽管糖皮质激素上调MKP-1水平，但它们不减弱该蛋白的蛋白酶体降解，因此它们不能抑制Erk-1/2活性。这些结果确定了MKP-1对糖皮质激素介导的Erk-1/2激活控制至关重要，并揭示了这种抗炎药物的新调控机制。
Glucocorticoids inhibit the proinflammatory activities of transcription factors such as AP-1 and NF-kappaB as well as that of diverse cellular signaling molecules. One of these signaling molecules is the extracellular signal-regulated kinase (Erk-1/2) that controls the release of allergic mediators and the induction of proinflammatory cytokine gene expression in mast cells. The mechanism of inhibition of Erk-1/2 activity by glucocorticoids is unknown. Here we report a novel dual action of glucocorticoids for this inhibition. Glucocorticoids increase the expression of the MAP kinase phosphatase-1 (MKP-1) gene at the promoter level, and attenuate proteasomal degradation of MKP-1, which we report to be triggered by activation of mast cells. Both induction of MKP-1 expression and inhibition of its degradation are necessary for glucocorticoid-mediated inhibition of Erk-1/2 activation. In NIH-3T3 fibroblasts, although glucocorticolds up-regulate the MKP-1 level, they do not attenuate the proteasomal degradation of this protein and consequently they are unable to inhibit Erk-1/2 activity. These results identify MKP-1 as essential for glucocorticoid-mediated control of Erk-1/2 activation and unravel a novel regulatory mechanism for this anti-inflammatory drug.