Effects of Glucocorticoid-Induced Transcript 1 Gene Deficiency on Glucocorticoid Activation in Asthmatic Mice.

Cheng-ping HU; Qiu-fen Xun; Xiao-zhao LI; Xin-yue HU; Ling Qin; Ruo-xi HE; Jun-tao Feng

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Effects of Glucocorticoid-Induced Transcript 1 Gene Deficiency on Glucocorticoid Activation in Asthmatic Mice.

Author: Cheng-Ping HU ¹ ; Qiu-Fen XUN ² ; Xiao-Zhao LI ³ ; Xin-Yue HU ¹ ; Ling QIN ¹ ; Ruo-Xi HE ¹ ; Jun-Tao FENG ¹
Author Information

1. 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.
2. Department of Respiratory Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
3. Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Publication Type:Journal Article
Keywords: Asthma; Glucocorticoid Receptor; Glucocorticoid-Induced Transcript 1; Glucocorticoids; Mitogen-Activated Protein Kinase Phosphatase-1
MeSH: Animals; Asthma; drug therapy; metabolism; Dual Specificity Phosphatase 1; genetics; metabolism; Forced Expiratory Volume; genetics; physiology; Glucocorticoids; therapeutic use; Mice; Mice, Knockout; Phosphorylation; genetics; physiology; Receptors, Glucocorticoid; deficiency; genetics; metabolism; p38 Mitogen-Activated Protein Kinases; genetics; metabolism
From: Chinese Medical Journal 2018;131(23):2817-2826
CountryChina
Language:English
Abstract: 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 (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.
Results: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).
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.