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A1311 - GLCCI1 Deficiency Downregulates the Glucocorticoids Activation in Asthmatic Mice
Author Block: J. Feng1, C. Hu1, Q. Xun1, X. Li2, X. Hu1, L. Luo1, L. Qin1, R. He1; 1Department of Respiratory Medicine (Department of Respiratory and Critical Care Medicine), Key Cite of National Clincial Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China, Changsha, China, 2Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China, Changsha, China.
Background: Glucocorticoid is the first line control for asthma, but some asthmatics are insensitive to it. Glucocorticoid-induced transcript 1 gene (GLCCI1) is reported to be associated with the sensitivity of glucocorticoids in asthmatics, while its exact mechanism remains unknown. In this study, we aim to explore possible mechanisms how GLCCI1 affects glucocorticoids efficiency in asthmatics. Methods: 30 asthmatic patients were recruited and received fluticasone propionate for 12 weeks. FEV1 and GLCCI1 mRNA expression were detected before and after 12 weeks’ treatment. In addition, asthma model was constructed in wild-type and GLCCI1 knock-out mice. The bronchial responsiveness, white blood cell counting in bronchoalveolar lavage and tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-6 (IL-6), IL-13 in lung tissue were detected. The glucocorticoid receptor (GR), Mitogen-activated protein kinase phosphatase 1 (MKP-1) expression were detected by real-time polymerase chain reaction (PCR) and western blot. The phosphorylation of p38 mitogen-activated protein kinase (MAPK) was also detected by western blot. Results: The change of FEV1 was well positively correlated with change of GLCCI1 mRNA expression in asthmatic patients. In the animal experiment, GLCCI1 knock-out asthmatic mice showed more serious airway hyperresponsiveness and inflammation, and glucocorticoids treatment had mild effect on them. GLCCI1 knock-out asthmatic mice had less improvement on GR and MKP-1 expression but more obvious phosphorylation of p38 MAPK under glucocorticoids treatment than those in wild-type asthmatic mice. Conclusions: GLCCI1 deficiency in asthmatic mice inhibits the activation of GR and MKP-1 and leads to more phosphorylation of p38 MAPK, leading to a decremental sensitivity to glucocorticoids.Trial Registration number: ChiCTR-RCC-13003634 www.chictr.org.cn Key words: asthma, GLCCI1, glucocorticoids, glucocorticoid receptor, Mitogen-activated protein kinase phosphatase 1