Inhibition of NF-κB-dependent Transcription by MKP-1 TRANSCRIPTIONAL REPRESSION BY GLUCOCORTICOIDS OCCURRING VIA p38 MAPK
Inhibition of NF-κB-dependent Transcription by MKP-1 TRANSCRIPTIONAL REPRESSION BY GLUCOCORTICOIDS OCCURRING VIA p38 MAPK
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DOI：
10.1074/jbc.m109.028381
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发表时间：
2009-09-25
影响因子：
4.8
通讯作者：
Newton, Robert
中科院分区：
文献类型：
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作者：
King, Elizabeth M.;Holden, Neil S.;Newton, Robert
糖皮质激素通过糖皮质激素受体（GR）发挥作用，部分通过抑制经由因子如NF-κ B发生的炎性基因转录来发挥有效的抗炎作用。在本研究中，合成的糖皮质激素地塞米松诱导人支气管上皮细胞（BEAS-2B）和肺细胞（A549）中MKP-1（丝裂原活化蛋白激酶（MAPK）磷酸酶-1）的表达。这与TNF α刺激的p38 MAPK磷酸化减少相关。由于NF-κ B依赖性转录和IL-8蛋白、mRNA和未剪接RNA（转录率的替代物）对p38 MAPK抑制剂（SB 203580和SB 239063）敏感，我们探索了MKP-1在抑制这些输出中的作用。地塞米松对TNF α诱导的p38 MAPK磷酸化、NF-κ B依赖性转录和IL-8表达的抑制对转录或翻译抑制剂敏感。这表明从头基因合成的作用。MKP-1的腺病毒表达显著降低p38 MAPK磷酸化和IL-8表达。类似地，NF-κ B依赖性转录显著降低至与最大p38 MAPK抑制一致的水平。因此，MKP-1减弱TNF α依赖性p38 MAPK活化、IL-8表达诱导和NF-κ B依赖性转录。地塞米松诱导的MKP-1表达的小干扰RNA敲低部分逆转了TNF α激活的p38 MAPK的抑制，表明MKP-1参与了该途径的地塞米松依赖性抑制。在存在MKK6（MAPK激酶6）（一种p38 MAPK激活剂）的情况下，地塞米松显著抑制TNF α诱导的NF-κ B依赖性转录，并且这被MKP-1靶向小干扰RNA显著逆转。这揭示了MKP-1的转录激活（反式激活）在糖皮质激素抑制NF-κ B依赖性转录中的重要和新颖作用。我们得出结论，GR反式激活是必不可少的GR配体的抗炎特性。
Acting via the glucocorticoid receptor (GR), glucocorticoids exert potent anti-inflammatory effects partly by repressing inflammatory gene transcription occurring via factors such as NF-kappa B. In the present study, the synthetic glucocorticoid, dexamethasone, induces expression of MKP-1 (mitogen-activated protein kinase (MAPK) phosphatase-1) in human bronchial epithelial (BEAS-2B) and pulmonary (A549) cells. This correlates with reduced TNF alpha-stimulated p38 MAPK phosphorylation. Since NF-kappa B-dependent transcription and IL-8 protein, mRNA, and unspliced RNA (a surrogate of transcription rate) are sensitive to p38 MAPK inhibitors (SB203580 and SB239063), we explored the role of MKP-1 in repression of these outputs. Repression of TNF alpha-induced p38 MAPK phosphorylation, NF-kappa B-dependent transcription, and IL-8 expression by dexamethasone are sensitive to transcriptional or translational inhibitors. This indicates a role for de novo gene synthesis. Adenoviral expression of MKP-1 profoundly reduces p38 MAPK phosphorylation and IL-8 expression. Similarly, NF-kappa B-dependent transcription is significantly reduced to levels consistent with maximal p38 MAPK inhibition. Thus, MKP-1 attenuates TNF alpha-dependent activation of p38 MAPK, induction of IL-8 expression, and NF-kappa B-dependent transcription. Small interfering RNA knockdown of dexamethasone-induced MKP-1 expression partially reverses the repression of TNF alpha-activated p38 MAPK, demonstrating that MKP-1 participates in the dexamethasone-dependent repression of this pathway. In the presence of MKK6 (MAPK kinase 6), a p38 MAPK activator, dexamethasone dramatically represses TNF alpha-induced NF-kappa B-dependent transcription, and this is significantly reversed by MKP-1-targeting small interfering RNA. This reveals an important and novel role for transcriptional activation (transactivation) of MKP-1 in the repression of NF-kappa B-dependent transcription by glucocorticoids. We conclude that GR transactivation is essential to the anti-inflammatory properties of GR ligands.