title: Down-regulation of GRα expression and inhibition of its nuclear translocation by hypoxia.
abstract: OBJECTIVE
  Glucocorticoids are the most effective anti-inflammatory agent in treating pulmonary diseases typically accompanied by hypoxia. Our previous study has demonstrated that glucocorticoid receptor α (GRα) expression is reduced in hypoxia but the underlying mechanism remains elusive. In this study we aim to identify the signaling pathway involved in hypoxia-induced down-regulation of GRα, and whether hypoxia affects nuclear translocation of GRα.
  
  
  METHODS
  Female C57BL/6 mice were sensitized with saline or ovalbumin (OVA) as the in vivo model. Mice were divided into control and OVA groups, and their lung histology and the expression of hypoxia inducible factor (HIF-1) and GRα were examined. A549 cells were exposed to chemical hypoxia as the in vitro model, where mitogen-activated protein kinases (MAPKs) were inhibited specifically by SB203580. Next, under normal or hypoxic conditions, the expression of GRα, MAPKs and HIF-1 signal protein were determined by Western blot analysis, and GRα translocation were observed through live-cell imaging.
  
  
  RESULTS
  In OVA challenged mice the expression of GRα was down-regulated whereas HIF-1 was up-regulated. Hypoxia caused a time-dependent decrease of GRα expression, and activated multiple signaling pathways including MAPKs and HIF-1. Moreover, GRα expression increased with MAPK inhibition. Interestingly, only MAPK inhibitor SB203580, but not JNK inhibitor SP600125 or ERK inhibitor U0126 improved the expression of GRα under hypoxic condition. GRα nuclear translocation was also significantly inhibited by hypoxia.
  
  
  CONCLUSIONS
  Hypoxia down-regulated the expression of GRα through p38 signaling pathway, as well as inhibited GRα nuclear translocation significantly.
authors.affiliation: Department of Pulmonary, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University.
authors.forename: Pei
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Pulmonary, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University.
authors.forename: Lei
authors.initials: L
authors.lastname: Fang
authors.affiliation: Department of Pulmonary, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University.
authors.forename: HuiMei
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Pulmonary, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University.
authors.forename: Peishan
authors.initials: P
authors.lastname: Ding
authors.affiliation: Department of Pulmonary, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University.
authors.forename: QiYing
authors.initials: Q
authors.lastname: Shen
authors.affiliation: Department of Pulmonary, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University.
authors.forename: Rongyu
authors.initials: R
authors.lastname: Liu
mesh_terms: D000818:Animals; D001249:Asthma / Q000503:physiopathology; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics; D016209:Interleukin-8 / Q000096:biosynthesis; D053612:Janus Kinases / Q000037:antagonists & inhibitors; D008168:Lung / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D010047:Ovalbumin / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis*; D014162:Transfection
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016209:Interleukin-8; D047428:Protein Kinase Inhibitors; D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha; D010047:Ovalbumin; D053612:Janus Kinases; D020928:Mitogen-Activated Protein Kinases
keywords: Glucocorticoids receptor; Hypoxia; Nuclear translocation; p38