Down-regulation of GRα expression and inhibition of its nuclear translocation by hypoxia.

Abstract

AIMS:

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.

MAIN 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.

KEY FINDINGS:

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.

SIGNIFICANCE:

Hypoxia down-regulated the expression of GRα through p38 signaling pathway, as well as inhibited GRα nuclear translocation significantly.

• Authors: Pei Zhang, Lei Fang, HuiMei Wu, Peishan Ding, QiYing Shen, Rongyu Liu
• Journal: Life sciences (Life Sci) Vol. 146 Pg. 92-9 (Feb 01 2016) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 26767627 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Interleukin-8
• Protein Kinase Inhibitors
• Receptors, Glucocorticoid
• glucocorticoid receptor alpha
• Ovalbumin
• Janus Kinases
• Mitogen-Activated Protein Kinases

Topics

• Animals
• Asthma (physiopathology)
• Down-Regulation (drug effects)
• Female
• Hypoxia (metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (biosynthesis, genetics)
• Interleukin-8 (biosynthesis)
• Janus Kinases (antagonists & inhibitors)
• Lung (pathology)
• MAP Kinase Signaling System (drug effects)
• Mice
• Mice, Inbred C57BL
• Mitogen-Activated Protein Kinases (antagonists & inhibitors)
• Ovalbumin (immunology)
• Protein Kinase Inhibitors (pharmacology)
• Protein Transport
• Receptors, Glucocorticoid (biosynthesis)
• Transfection