Abnormal glucocorticoid receptor-activator protein 1 interaction in steroid-resistant asthma.
Abnormal glucocorticoid receptor-activator protein 1 interaction in steroid-resistant asthma.
复制标题
糖皮质激素受体激活蛋白1在类固醇哮喘中的相互作用。
DOI：
10.1084/jem.182.6.1951
复制
发表时间：
1995-12-01
影响因子：
15.3
通讯作者：
Barnes, Peter J.
中科院分区：
文献类型：
--
作者：
Adcock, Ian M.;Lane, Stephen J.;Brown, Carolanne R.;Lee, Tak H.;Barnes, Peter J.
糖皮质激素是治疗哮喘和其他慢性炎症性疾病的非常有效的方法。然而，一小部分患者对糖皮质激素的治疗效果有抵抗力。药代动力学和配体结合研究表明类固醇抗性的分子异常位于核易位的远端。我们之前报道过，地塞米松治疗后，糖皮质激素受体 (GR) 与外周血单核细胞 (PBMC) 中 DNA 结合位点的结合能力下降。 DNA 结合的减少是由于可用受体数量的减少，而不是由于 DNA 亲和力的改变。为了研究这种减少的 DNA 结合，我们检查了核转位转录因子激活蛋白 1 (AP-1)、核因子 kappa B (NF-kappa B) 和环 AMP 反应元件结合蛋白 (CREB) 与其 DNA 结合位点结合的能力，以及与类固醇敏感和类固醇抵抗性哮喘患者的 PBMC 中 GR 相互作用的能力。在这些类固醇抵抗患者中，GR 和 AP-1 之间的相互作用显着减少，尽管与炎症中激活的其他转录因子（NF-κ B 和 CREB）的相互作用不受影响。在类固醇抵抗性哮喘患者的细胞核中也检测到 AP-1 DNA 结合的基础水平有所增加。 AP-1、c-Fos 和 c-Jun 成分中检测到的信使 RNA 量没有差异，这些信使 RNA 的序列也没有差异。这些结果表明，在类固醇抵抗患者中，GR 与糖皮质激素反应元件和 AP-1 结合的能力发生了改变，或者 AP-1 水平增加阻止了 GR DNA 结合，这可能是这些细胞中对类固醇抗炎作用产生抵抗的分子基础。
Glucocorticosteroids are a very effective treatment for asthma and other chronic inflammatory diseases. However, a small proportion of patients is resistant to the therapeutic effects of glucocorticoids. Pharmacokinetic and ligand binding studies suggest that the molecular abnormality in steroid resistance lies distal to nuclear translocation. We have previously reported that there is a decreased ability of glucocorticoid receptors (GR) to bind to the DNA-binding site in peripheral blood mononuclear cells (PBMC) after dexamethasone treatment. This reduced DNA binding was due to a decrease in the number of receptors available rather than an alteration in affinity for DNA. To study this reduced DNA binding, we examined the ability of the nuclear translocated transcription factors activator protein 1 (AP-1), nuclear factor kappa B (NF-kappa B) and cyclic AMP response element- binding protein (CREB) to bind to their DNA-binding sites and to interact with GR in PBMC from patients with steroid-sensitive and steroid-resistant asthma. There was a significant reduction in the interaction between GR and AP-1 in these steroid-resistant patients, although interaction with other transcription factors activated in inflammation (NF-kappa B and CREB) was unaffected. An increase in the basal levels of AP-1 DNA binding was also detected in the nuclei from steroid-resistant asthmatic patients. There were no differences in the amount of messenger RNA detected for the components of AP-1, c-Fos and c-Jun, nor in the sequences of these messenger RNAs. These results suggest either that the ability of the GR to bind to glucocorticoid response elements and AP-1 is altered in steroid-resistant patients or that increased levels of AP-1 prevent GR DNA binding, and that this may be the molecular basis of resistance to the antiinflammatory effect of steroids in these cells.
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影响因子：
14.9
作者：
ARCARI, P;MARTINELLI, R;SALVATORE, F
通讯作者：
SALVATORE, F
影响因子：
105.7
作者：
CARMICHAEL, J;PATERSON, IC;GRANT, IWB
通讯作者：
GRANT, IWB
DOI：
10.1164/ajrccm/144.5.page
发表时间：
1991-11-01
期刊：
AMERICAN REVIEW OF RESPIRATORY DISEASE
影响因子：
--
作者：
CORRIGAN, CJ;BROWN, PH;KAY, AB
通讯作者：
KAY, AB
影响因子：
2.9
作者：
GOUGH, NM
通讯作者：
GOUGH, NM
影响因子：
64.5
作者：
SCHULE, R;RANGARAJAN, P;EVANS, RM
通讯作者：
EVANS, RM