GLCCI1 Deficiency Induces Glucocorticoid Resistance via the Competitive Binding of IRF1:GRIP1 and IRF3:GRIP1 in Asthma.
GLCCI1 Deficiency Induces Glucocorticoid Resistance via the Competitive Binding of IRF1:GRIP1 and IRF3:GRIP1 in Asthma.
复制标题
哮喘中 GLCCI1 缺乏通过 IRF1:GRIP1 和 IRF3:GRIP1 的竞争性结合诱导糖皮质激素抵抗
DOI：
10.3389/fmed.2021.686493
复制
发表时间：
2021
影响因子：
3.9
通讯作者：
Feng J
中科院分区：
文献类型：
--
作者：
Hu X;Deng S;Luo L;Jiang Y;Ge H;Yin F;Zhang Y;Zhang D;Li X;Feng J
GLCCI 1在调节哮喘患者糖皮质激素（GC）敏感性方面发挥重要作用。本项目确定了GLCCI 1缺陷通过上调IRF 1：GRIP 1和IRF 3：GRIP 1的结合来减弱地塞米松（Dex）处理的卵清蛋白（OVA）诱导的哮喘小鼠和上皮细胞的GC敏感性的潜在机制。与野生型哮喘小鼠相比，地塞米松治疗导致炎症、气道高反应性和负责GC活性的组分的活化减少较少，这通过降低GR和糖皮质激素受体相互作用蛋白1（GRIP 1）表达而确定，但增加了GLCCI 1 −/−哮喘小鼠中IRF 1和IRF 3的表达。此外，与野生型Dex治疗的哮喘小鼠相比，GLCCI 1 −/− Dex治疗的哮喘小鼠中GRIP 1向GR的募集下调，而GRIP 1向IRF 1和IRF 3的个体募集上调。我们还发现GLCCI 1敲低降低了Beas 2B和A549细胞中GR和GRIP 1的表达，但增加了IRF 1和IRF 3的表达。此外，GLCCI 1沉默增加了GRIP 1与IRF 1和GRIP 1与IRF 3之间的相互作用，但减少了GRIP 1向GR的募集。这些研究支持了哮喘GC反应中GLCCI 1表达对上皮细胞的重要但以前未被认识的作用，其中GLCCI 1缺乏减少了GR和GRIP 1的相互作用，但竞争性地增强了GRIP 1向IRF 1和IRF 3的募集。
GLCCI1 plays a significant role in modulating glucocorticoid (GC) sensitivity in asthma. This project determines the underlying mechanism that GLCCI1 deficiency attenuates GC sensitivity in dexamethasone (Dex)-treated Ovalbumin (OVA)-induced asthma mice and epithelial cells through upregulating binding of IRF1:GRIP1 and IRF3:GRIP1. Dexamethasone treatment led to less reduced inflammation, airway hyperresponsiveness, and activation of the components responsible for GC activity, as determined by decreased GR and glucocorticoid receptor interacting protein 1 (GRIP1) expression but augmented IRF1 and IRF3 expression in GLCCI1−/− asthmatic mice compared with wild type asthmatic mice. Moreover, the recruitment of GRIP1 to GR was downregulated, while the individual recruitment of GRIP1 to IRF1 and IRF3 was upregulated in GLCCI1−/− Dex-treated asthmatic mice compared to wild type Dex-treated asthmatic mice. We also found that GLCCI1 knockdown reduced GR and GRIP1 expression but increased IRF1 and IRF3 expression in Beas2B and A549 cells. Additionally, GLCCI1 silencing increased the interactions between GRIP1 with IRF1 and GRIP1 with IRF3, but decreased the recruitment of GRIP1 to GR. These studies support a critical but previously unrecognized effect of GLCCI1 expression on epithelial cells in asthma GC responses by which GLCCI1 deficiency reduces the GR and GRIP1 interaction but competitively enhances the recruitment of GRIP1 to IRF1 and IRF3.
登录
查看更多内容
糖皮质激素诱导的转录物 1 基因缺陷对哮喘小鼠糖皮质激素激活的影响
影响因子：
6.1
作者：
Hu CP;Xun QF;Li XZ;Hu XY;Qin L;He RX;Feng JT
通讯作者：
Feng JT
DOI：
10.1056/nejmoa0911353
发表时间：
2011-09-29
期刊：
The New England journal of medicine
影响因子：
--
作者：
Tantisira KG;Lasky-Su J;Harada M;Murphy A;Litonjua AA;Himes BE;Lange C;Lazarus R;Sylvia J;Klanderman B;Duan QL;Qiu W;Hirota T;Martinez FD;Mauger D;Sorkness C;Szefler S;Lazarus SC;Lemanske RF Jr;Peters SP;Lima JJ;Nakamura Y;Tamari M;Weiss ST
通讯作者：
Weiss ST
影响因子：
2.6
作者：
Chapin, William J.;Lenkala, Divya;Huang, Rong S.
通讯作者：
Huang, Rong S.
影响因子：
5.3
作者：
Hong, H;Kohli, K;Stallcup, MR
通讯作者：
Stallcup, MR
DOI：
10.1038/nrm.2016.152
发表时间：
2017-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Weikum ER;Knuesel MT;Ortlund EA;Yamamoto KR
通讯作者：
Yamamoto KR