Department of Respiratory and Critical Care Medicine, Key Cite of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Department of Respiratory Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
Chin Med J (Engl). 2018 Dec 5;131(23):2817-2826. doi: 10.4103/0366-6999.246061.
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.
A total of 30 asthmatic patients received fluticasone propionate for 12 weeks. Forced expiratory volume in 1 s (FEV) 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.
In asthmatic patients, the change of FEV 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).
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.
ChiCTR.org.cn, ChiCTR-RCC-13003634; http://www.chictr.org.cn/showproj.aspx?proj=5926.
糖皮质激素（GC）是哮喘的一线治疗药物，但有些哮喘患者对此不敏感。糖皮质激素诱导转录物 1 基因（GLCCI1）据报道与哮喘患者 GC 的疗效有关，但确切机制尚不清楚。
30 例哮喘患者接受丙酸氟替卡松治疗 12 周。检测第 1 秒用力呼气量（FEV）和 GLCCI1 表达。在野生型和 GLCCI1 敲除（GLCCI1）小鼠中构建哮喘模型。通过聚合酶链反应和 Western blot（WB）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。还通过 WB 检测 p38 丝裂原活化蛋白激酶（MAPK）的磷酸化。
在哮喘患者中，FEV 的变化与 GLCCI1 表达的变化呈良好的正相关（r=0.430，P=0.022）。在动物实验中，与对照组相比，哮喘小鼠的 GR 和 MKP-1 mRNA 水平显著降低（野生型：GR：0.769 比 1.000，P=0.022；MKP-1：0.493 比 1.000，P<0.001。GLCCI1：GR：0.629 比 1.645，P<0.001；MKP-1：0.377 比 2.146，P<0.001）。水泼尼松治疗后，GR 和 MKP-1 mRNA 表达水平明显高于哮喘组；然而，GLCCI1 哮喘小鼠的改善程度较小（野生型：GR：1.517 比 0.769，P=0.023；MKP-1：1.036 比 0.493，P=0.003。GLCCI1：GR：0.846 比 0.629，P=0.116；MKP-1：0.475 比 0.377，P=0.388）。GLCCI1 哮喘小鼠 p38 MAPK 的磷酸化比野生型哮喘小鼠更明显（9.060 比 3.484，P<0.001）。即使在水泼尼松治疗后，它仍然更高（6.440 比 2.630，P<0.001）。
哮喘小鼠中 GLCCI1 的缺失抑制了 GR 和 MKP-1 的激活，导致 p38 MAPK 的磷酸化更明显，导致对 GCs 的敏感性降低。
ChiCTR.org.cn，ChiCTR-RCC-13003634；http://www.chictr.org.cn/showproj.aspx?proj=5926。
