Importin 13 regulates nuclear import of the glucocorticoid receptor in airway epithelial cells
Importin 13 regulates nuclear import of the glucocorticoid receptor in airway epithelial cells
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DOI：
10.1165/rcmb.2006-0073oc
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发表时间：
2006-12-01
影响因子：
6.4
通讯作者：
Kaplan, Feige
中科院分区：
文献类型：
--
作者：
Tao, Tao;Lan, Jie;Kaplan, Feige
糖皮质激素的抗炎作用对治疗哮喘等常见疾病的气道炎症至关重要。对糖皮质激素的反应有相当大的差异，长期暴露可导致糖皮质激素抵抗。我们在胎鼠肺中克隆了含糖皮质激素基因LGL2。我们描述了IgI2作为核转运蛋白的特征，归类为输入蛋白13 (IPO13)，并证明了IPO13核胞质穿梭的发育调控。我们现在报告了糖皮质激素受体（GR）作为IP013的货物底物的鉴定。GR- gst下拉和共免疫沉淀证实了GR与IP013的结合。为了研究IP013在肺中调节GIR信号的作用，我们研究了IP013在气道上皮细胞中调节的GIR运输。抑制IP013合成的小干扰rna阻止了GIR的核易位。IP013的沉默也取消了皮质醇在tnf - α刺激后抑制炎症细胞因子IL-8合成的能力。我们的研究结果支持IP013在促进GIR核占用方面的作用，这种方式强烈增强了糖皮质激素的抗炎作用。我们推测IP013细胞水平和细胞内IP013穿梭率的变化可能有助于糖皮质激素抵抗。
Antiinflammatory effects of glucocorticoids are critical to treatment of airway inflammation in such common disorders as asthma. There is considerable variation in responsiveness to glucocorticoid, and prolonged exposure can result in glucocorticoid resistance. We cloned LGL2, a glucocorticoid-inclucible gene in fetal rat lung. We described the characterization of IgI2 as a nuclear transport protein, classified as importin 13 (IPO13), and demonstrated developmental regulation of IP013 nucleocytoplasmic shuttling. We now report on the identification of the glucocorticoid receptor (GR) as a cargo substrate for IP013. Binding of GR and IP013 was demonstrated by GR-GST pulldown and coimmunoprecipitation. To investigate the role of IP013 in modulating GIR signaling in the lung, we studied IPO13-regulated GIR transport in airway epithelial cells. Small interfering RNAs that inhibited IP013 synthesis prevented nuclear translocation of GIR. Silencing of IP013 also abrogated the ability of cortisol to inhibit synthesis of the inflammatory cytokine IL-8 after stimulation with TNF-alpha. Our findings support a role for IP013 in promoting nuclear-occupancy of GIR in a way that strongly potentiates the antiinflammatory effects of glucocorticoids. We speculate that variation in cellular levels of IP013 and intracellular IP013 shuttling rates may contribute to glucocorticoid resistance.