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ORIGINAL ARTICLE
Year : 2018  |  Volume : 131  |  Issue : 23  |  Page : 2817-2826

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


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

Correspondence Address:
Dr. Jun-Tao Feng
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
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0366-6999.246061

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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.

 

 Abstract in Chinese

GLCCI1基因敲除参与支气管哮喘小鼠糖皮质激素通路活化下调

摘要

背景:糖皮质激素是支气管哮喘治疗的一线药物,但部分哮喘患者对激素不敏感。研究发现,糖皮质激素诱导的转录基因1(GLCCI1)与哮喘患者糖皮质激素疗效有关,但其具体机制尚不明确。

方法:30例哮喘患者接受为期12周的丙酸氟替卡松吸入治疗,检测FEV1及GLCCI1表达水平。利用野生型及GLCCI1基因敲除小鼠构建哮喘模型。造模成功后,通过PCR及Western blotting检测肺组织中GR、MKP-1表达水平;Western blotting检测p38 MAPK信号通路的磷酸化程度.

结果:哮喘患者经丙酸氟替卡松吸入治疗后FEV1改变量与GLCCI1 mRNA表达水平改变量呈正相关(r = 0.430, P = 0.022)。在动物实验中,哮喘小鼠肺组织GRMKP-1 mRNA表达水平低于对照组(野生型组: GR:0.769 vs. 1.000,P = 0.022; MKP-1:0.493 vs. 1.000,P < 0.001; GLCCI1-/-组: GR:0.629 vs. 1.645,P < 0.001;MKP-1:0.377 vs. 2.146 ,P <0.001 )。与哮喘组小鼠相比,经氢化泼尼松治疗后的哮喘小鼠GRMKP-1 mRNA表达水平显著升高,但GLCCI1-/-组升高程度低于野生型组(野生型组: GR: 1.517 vs. 0.769, P = 0.023; MKP-1: 1.036 vs. 0.493, P = 0.003. GLCCI1-/-组: GR: 0.846 vs. 0.629, P = 0.116; MKP-1: 0.475 vs. 0.377, P = 0.388)。与野生型哮喘小鼠相比,GLCCI1基因敲除哮喘小鼠p38 MAPK磷酸化水平升高 (9.060 vs. 3.484, P <0.001)。经氢化泼尼松治疗后GLCCI1基因敲除哮喘小鼠p38 MAPK磷酸化水平仍高于野生型哮喘小鼠(6.440 vs. 2.630, P <0.001)。

结论GLCCI1基因消除哮喘小鼠GR及MKP-1表达受抑制,导致p38 MAPK磷酸化,从而导致糖皮质激素敏感性下降。



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