Interleukin 1α (IL-1α) induced activation of p38 mitogen-activated protein kinase inhibits glucocorticoid receptor function
Interleukin 1α (IL-1α) induced activation of p38 mitogen-activated protein kinase inhibits glucocorticoid receptor function
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DOI：
10.1038/sj.mp.4001339
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发表时间：
2004-01-01
影响因子：
11
通讯作者：
Miller, AH
中科院分区：
文献类型：
--
作者：
Wang, X;Wu, H;Miller, AH
先前的研究表明，白细胞介素α (il -1 α)抑制糖皮质激素受体（GR）核易位和地塞米松（Dex）诱导的基因转录。鉴于il -1 α是p38丝裂原活化蛋白激酶（MAPK）信号转导途径的有效激活因子，且p38 MAPK与GR功能降低有关，我们在稳定转染GR介导的报告基因构建物（LMCAT细胞）的小鼠成纤维细胞中研究了p38 MAPK在il -1 α介导的GR功能抑制中的作用。il -1 α (1000 U/ml)处理LMCAT细胞24 h后，Dex （50 nM）诱导的gr - cat活性下降35%左右。当细胞与IL-1alpha和选择性p38抑制剂SB-203580 （0.5-1 muM）共处理24 h时，IL-1alpha对GR功能的抑制作用（通过dex诱导的GR - cat活性测定）被逆转。通过凝胶迁移迁移实验，SB-203580也被发现可以逆转il -1 α对GR-GRE结合的抑制。进一步证实p38通路的作用，用针对p38 MAPK的反义寡核苷酸预处理LMCAT细胞，完全消除了il -1 α对dex诱导的gr - cat活性的抑制作用。综上所述，这些结果表明p38 MAPK通路的激活参与了il -1 α介导的GR功能抑制。此外，这些发现将p38的细胞内靶标扩展到包括GR，并表明p38抑制剂可能在与GR介导的反馈抑制受损相关的免疫和/或神经精神疾病中具有特殊用途。
Previous studies have demonstrated that interleukinalpha (IL-1alpha) inhibits glucocorticoid receptor (GR) nuclear translocation and dexamethasone (Dex)-induced gene transcription. Given that IL-1alpha is a potent activator of the p38 mitogen-activated protein kinase (MAPK) signal transduction pathway and p38 MAPK has been associated with reduced GR function, we examined the role of p38 MAPK in IL-1alpha-mediated inhibition of GR function in mouse fibroblast cells stably transfected with a GR-mediated reporter gene construct (LMCAT cells). Treatment of LMCAT cells with IL-1alpha (1000 U/ml) for 24 h inhibited Dex (50 nM)-induced GRE-CAT activity by similar to35%. When cells were cotreated for 24 h with IL-1alpha plus SB-203580 (0.5-1 muM), a selective p38 inhibitor, IL-1alpha's inhibitory effect on GR function as determined by Dex-induced GRE-CAT activity was reversed. Using gel mobility shift assay, SB-203580 was also found to reverse IL-1alpha inhibition of GR-GRE binding. Further confirming the role of p38 pathways, pretreatment of LMCAT cells with antisense oligonucleotides targeted to p38 MAPK completely abrogated IL-1alpha inhibition of Dex-induced GRE-CAT activity. Taken together, these results demonstrate that activation of p38 MAPK pathways are involved in IL-1alpha-mediated inhibition of GR function. In addition, these findings extend the intracellular targets of p38 to include the GR and indicate that p38 inhibitors may have special utility in immunologic and/or neuropsychiatric disorders associated with impaired GR-mediated feedback inhibition.