Effects of Glucocorticoid-Induced Transcript 1 Gene Deficiency on Glucocorticoid Activation in Asthmatic Mice.
Effects of Glucocorticoid-Induced Transcript 1 Gene Deficiency on Glucocorticoid Activation in Asthmatic Mice.
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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
DOI：
10.4103/0366-6999.246061
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发表时间：
2018-12-05
影响因子：
6.1
通讯作者：
Feng JT
中科院分区：
文献类型：
--
作者：
Hu CP;Xun QF;Li XZ;Hu XY;Qin L;He RX;Feng JT
背景资料：糖皮质激素（Glucocorticoid，GC）是治疗哮喘的一线药物，但部分哮喘患者对GC不敏感，糖皮质激素诱导的转录本1（Glucocorticoid induced transcript 1，GLCCI 1）基因与GC疗效相关，但其确切机制尚不清楚。方法：30例哮喘患者接受丙酸氟替卡松治疗12周。检测1秒用力呼气量（FEV 1）和GLCCI 1的表达。在野生型和GLCCI 1敲除（GLCCI 1-/-）小鼠中构建哮喘模型。采用聚合酶链反应和蛋白质印迹法检测糖皮质激素受体（GR）和丝裂原活化蛋白激酶磷酸酶1（MKP-1）的表达。WB法检测p38丝裂原活化蛋白激酶（MAPK）的磷酸化。结果：哮喘患者FEV 1变化与GLCCI 1表达变化呈显著正相关（r = 0.430，P = 0.022）。动物实验中，哮喘小鼠GR和MKP-1的mRNA水平均较对照组显著降低（野生型：GR：0.769 vs. 1.000，P = 0.022; MKP-1：0.493 vs. 1.000，P < 0.001）。GLCCI 1-/-：GR：0.629 vs. 1.645，P < 0.001; MKP-1：0.377 vs. 2.146，P < 0.001）。与哮喘组相比，氢化泼尼松治疗显著增加了GR和MKP-1 mRNA表达水平;然而，GLCCI 1-/-哮喘小鼠的改善较少（野生型：GR：1.517 vs. 0.769，P = 0.023; MKP-1：1.036 vs. 0.493，P = 0.003）。GLCCI 1-/-：GR：0.846 vs. 0.629，P = 0.116; MKP-1：0.475 vs. 0.377，P = 0.388）。GLCCI 1-/-哮喘小鼠p38 MAPK磷酸化水平明显高于野生型哮喘小鼠（9.060 vs.3.484，P < 0.001）。经激素治疗后仍高于对照组（6.440 vs.2.630，P < 0.001）。结论：哮喘小鼠中GLCCI 1缺乏抑制GR和MKP-1的活化，导致p38 MAPK磷酸化更明显，从而导致对GC的敏感性降低。试验注册：ChiCTR.org.cn，ChiCTR-RCC-13003634; http://www.chictr.org.cn/showproj.aspx? proj=5926。
Background: Glucocorticoid (GC) is the first-line therapy for asthma, but some asthmatics are insensitive to it. Glucocorticoid-induced transcript 1 gene (GLCCI1) is reported to be associated with GCs efficiency in asthmatics, while its exact mechanism remains unknown. Methods: A total of 30 asthmatic patients received fluticasone propionate for 12 weeks. Forced expiratory volume in 1 s (FEV1) and GLCCI1 expression were detected. Asthma model was constructed in wild-type and GLCCI1 knockout (GLCCI1-/-) mice. Glucocorticoid receptor (GR) and mitogen-activated protein kinase phosphatase 1 (MKP-1) expression were detected by polymerase chain reaction and Western blotting (WB). The phosphorylation of p38 mitogen-activated protein kinase (MAPK) was also detected by WB. Results: In asthmatic patients, the change of FEV1 was well positively correlated with change of GLCCI1 expression (r = 0.430, P = 0.022). In animal experiment, GR and MKP-1 mRNA levels were significantly decreased in asthmatic mice than in control mice (wild-type: GR: 0.769 vs. 1.000, P = 0.022; MKP-1: 0.493 vs. 1.000, P < 0.001. GLCCI1-/-: GR: 0.629 vs. 1.645, P < 0.001; MKP-1: 0.377 vs. 2.146, P < 0.001). Hydroprednisone treatment significantly increased GR and MKP-1 mRNA expression levels than in asthmatic groups; however, GLCCI1-/- asthmatic mice had less improvement (wild-type: GR: 1.517 vs. 0.769, P = 0.023; MKP-1: 1.036 vs. 0.493, P = 0.003. GLCCI1-/-: GR: 0.846 vs. 0.629, P = 0.116; MKP-1: 0.475 vs. 0.377, P = 0.388). GLCCI1-/- asthmatic mice had more obvious phosphorylation of p38 MAPK than wild-type asthmatic mice (9.060 vs. 3.484, P < 0.001). It was still higher even though after hydroprednisone treatment (6.440 vs. 2.630, P < 0.001). Conclusions: GLCCI1 deficiency in asthmatic mice inhibits the activation of GR and MKP-1 and leads to more obvious phosphorylation of p38 MAPK, leading to a decremental sensitivity to GCs. Trial Registration: ChiCTR.org.cn, ChiCTR-RCC-13003634; http://www.chictr.org.cn/showproj.aspx?proj=5926.
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影响因子：
2.1
作者：
Suvanto M;Jahnukainen T;Kestilä M;Jalanko H
通讯作者：
Jalanko H
影响因子：
20.3
作者：
Bhattacharyya, Sandip;Brown, Diane E.;Muglia, Louis J.
通讯作者：
Muglia, Louis J.
影响因子：
4
作者：
Quax, R. A. M.;Koper, J. W.;Huisman, A. M.;Weel, A.;Hazes, J. M. W.;Lamberts, S. W. J.;Feelders, R. A.
通讯作者：
Feelders, R. A.
影响因子：
--
作者：
Jang, Byeong-Churl;Lim, Ki-Jo;Suh, Seong-Il
通讯作者：
Suh, Seong-Il
影响因子：
9.3
作者：
Pignatti, PF
通讯作者：
Pignatti, PF