Glucocorticoid protection of oligodendrocytes against excitotoxin involving hypoxia-inducible factor-1α in a cell-type-specific manner

Yu Yo Sun, Chen Yu Wang, Ming Feng Hsu, Shu Hui Juan, Chiu Yun Chang, Chih Ming Chou, Liang Yo Yang, Kuo Sheng Hung, Jan Xu, Yi-Hsuan Lee, Chung-Yi Hsu

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Glucocorticoids are commonly used in treating diseases with white matter lesions, including demyelinating diseases and spinal cord injury (SCI). However, glucocorticoids are ineffective in gray matter injuries, such as head injury and stroke. The differential glucocorticoid effects in white and gray matter injuries are unclear. We report here a novel mechanism of methylprednisolone (MP), a synthetic glucocorticoid widely used for treating multiple sclerosis and SCI, in protecting oligodendrocytes (OLGs) against AMPA-induced excitotoxicity, which has been implicated in the white matter injuries and diseases. The cytoprotective action of MP in OLGs is causally related to its upregulation of a neuroprotective cytokine erythropoietin (Epo). MP transactivation of Epo expression involves dual transcription factors: glucocorticoid receptor (GR) and hypoxia-inducible factor-1α (HIF-1α). Coimmunoprecipitation, chromatin immunoprecipitation analysis, yeast two-hybrid analysis, and structure modeling of three-dimensional protein - protein interactions confirm that MP induces interaction between GR DNA binding domain and HIF-1α PAS domain, with subsequent recruitment of HIF-1β to transactivate Epo expression in OLGs. In contrast, MP activates GR but does not induce GR-HIF-1α interaction, HIF-1α binding to Epo enhancer/ promoter, or Epo expression in cultured cortical neurons. The OLG-specific GR-HIF-1α transactivation of Epo provides novel insights into the development of more effective therapies for diseases affecting the white matter.

Original languageEnglish
Pages (from-to)9621-9630
Number of pages10
JournalJournal of Neuroscience
Volume30
Issue number28
DOIs
Publication statusPublished - Jul 14 2010

Fingerprint

Hypoxia-Inducible Factor 1
Oligodendroglia
Neurotoxins
Erythropoietin
Glucocorticoid Receptors
Glucocorticoids
Methylprednisolone
Spinal Cord Injuries
Transcriptional Activation
Wounds and Injuries
Leukoencephalopathies
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Chromatin Immunoprecipitation
Demyelinating Diseases
Craniocerebral Trauma
Multiple Sclerosis
Proteins
Transcription Factors
Up-Regulation
Yeasts

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Glucocorticoid protection of oligodendrocytes against excitotoxin involving hypoxia-inducible factor-1α in a cell-type-specific manner. / Sun, Yu Yo; Wang, Chen Yu; Hsu, Ming Feng; Juan, Shu Hui; Chang, Chiu Yun; Chou, Chih Ming; Yang, Liang Yo; Hung, Kuo Sheng; Xu, Jan; Lee, Yi-Hsuan; Hsu, Chung-Yi.

In: Journal of Neuroscience, Vol. 30, No. 28, 14.07.2010, p. 9621-9630.

Research output: Contribution to journalArticle

Sun, Yu Yo ; Wang, Chen Yu ; Hsu, Ming Feng ; Juan, Shu Hui ; Chang, Chiu Yun ; Chou, Chih Ming ; Yang, Liang Yo ; Hung, Kuo Sheng ; Xu, Jan ; Lee, Yi-Hsuan ; Hsu, Chung-Yi. / Glucocorticoid protection of oligodendrocytes against excitotoxin involving hypoxia-inducible factor-1α in a cell-type-specific manner. In: Journal of Neuroscience. 2010 ; Vol. 30, No. 28. pp. 9621-9630.
@article{e359de15f7d64d7e8191e7d9a52642e7,
title = "Glucocorticoid protection of oligodendrocytes against excitotoxin involving hypoxia-inducible factor-1α in a cell-type-specific manner",
abstract = "Glucocorticoids are commonly used in treating diseases with white matter lesions, including demyelinating diseases and spinal cord injury (SCI). However, glucocorticoids are ineffective in gray matter injuries, such as head injury and stroke. The differential glucocorticoid effects in white and gray matter injuries are unclear. We report here a novel mechanism of methylprednisolone (MP), a synthetic glucocorticoid widely used for treating multiple sclerosis and SCI, in protecting oligodendrocytes (OLGs) against AMPA-induced excitotoxicity, which has been implicated in the white matter injuries and diseases. The cytoprotective action of MP in OLGs is causally related to its upregulation of a neuroprotective cytokine erythropoietin (Epo). MP transactivation of Epo expression involves dual transcription factors: glucocorticoid receptor (GR) and hypoxia-inducible factor-1α (HIF-1α). Coimmunoprecipitation, chromatin immunoprecipitation analysis, yeast two-hybrid analysis, and structure modeling of three-dimensional protein - protein interactions confirm that MP induces interaction between GR DNA binding domain and HIF-1α PAS domain, with subsequent recruitment of HIF-1β to transactivate Epo expression in OLGs. In contrast, MP activates GR but does not induce GR-HIF-1α interaction, HIF-1α binding to Epo enhancer/ promoter, or Epo expression in cultured cortical neurons. The OLG-specific GR-HIF-1α transactivation of Epo provides novel insights into the development of more effective therapies for diseases affecting the white matter.",
author = "Sun, {Yu Yo} and Wang, {Chen Yu} and Hsu, {Ming Feng} and Juan, {Shu Hui} and Chang, {Chiu Yun} and Chou, {Chih Ming} and Yang, {Liang Yo} and Hung, {Kuo Sheng} and Jan Xu and Yi-Hsuan Lee and Chung-Yi Hsu",
year = "2010",
month = "7",
day = "14",
doi = "10.1523/JNEUROSCI.2295-10.2010",
language = "English",
volume = "30",
pages = "9621--9630",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "28",

}

TY - JOUR

T1 - Glucocorticoid protection of oligodendrocytes against excitotoxin involving hypoxia-inducible factor-1α in a cell-type-specific manner

AU - Sun, Yu Yo

AU - Wang, Chen Yu

AU - Hsu, Ming Feng

AU - Juan, Shu Hui

AU - Chang, Chiu Yun

AU - Chou, Chih Ming

AU - Yang, Liang Yo

AU - Hung, Kuo Sheng

AU - Xu, Jan

AU - Lee, Yi-Hsuan

AU - Hsu, Chung-Yi

PY - 2010/7/14

Y1 - 2010/7/14

N2 - Glucocorticoids are commonly used in treating diseases with white matter lesions, including demyelinating diseases and spinal cord injury (SCI). However, glucocorticoids are ineffective in gray matter injuries, such as head injury and stroke. The differential glucocorticoid effects in white and gray matter injuries are unclear. We report here a novel mechanism of methylprednisolone (MP), a synthetic glucocorticoid widely used for treating multiple sclerosis and SCI, in protecting oligodendrocytes (OLGs) against AMPA-induced excitotoxicity, which has been implicated in the white matter injuries and diseases. The cytoprotective action of MP in OLGs is causally related to its upregulation of a neuroprotective cytokine erythropoietin (Epo). MP transactivation of Epo expression involves dual transcription factors: glucocorticoid receptor (GR) and hypoxia-inducible factor-1α (HIF-1α). Coimmunoprecipitation, chromatin immunoprecipitation analysis, yeast two-hybrid analysis, and structure modeling of three-dimensional protein - protein interactions confirm that MP induces interaction between GR DNA binding domain and HIF-1α PAS domain, with subsequent recruitment of HIF-1β to transactivate Epo expression in OLGs. In contrast, MP activates GR but does not induce GR-HIF-1α interaction, HIF-1α binding to Epo enhancer/ promoter, or Epo expression in cultured cortical neurons. The OLG-specific GR-HIF-1α transactivation of Epo provides novel insights into the development of more effective therapies for diseases affecting the white matter.

AB - Glucocorticoids are commonly used in treating diseases with white matter lesions, including demyelinating diseases and spinal cord injury (SCI). However, glucocorticoids are ineffective in gray matter injuries, such as head injury and stroke. The differential glucocorticoid effects in white and gray matter injuries are unclear. We report here a novel mechanism of methylprednisolone (MP), a synthetic glucocorticoid widely used for treating multiple sclerosis and SCI, in protecting oligodendrocytes (OLGs) against AMPA-induced excitotoxicity, which has been implicated in the white matter injuries and diseases. The cytoprotective action of MP in OLGs is causally related to its upregulation of a neuroprotective cytokine erythropoietin (Epo). MP transactivation of Epo expression involves dual transcription factors: glucocorticoid receptor (GR) and hypoxia-inducible factor-1α (HIF-1α). Coimmunoprecipitation, chromatin immunoprecipitation analysis, yeast two-hybrid analysis, and structure modeling of three-dimensional protein - protein interactions confirm that MP induces interaction between GR DNA binding domain and HIF-1α PAS domain, with subsequent recruitment of HIF-1β to transactivate Epo expression in OLGs. In contrast, MP activates GR but does not induce GR-HIF-1α interaction, HIF-1α binding to Epo enhancer/ promoter, or Epo expression in cultured cortical neurons. The OLG-specific GR-HIF-1α transactivation of Epo provides novel insights into the development of more effective therapies for diseases affecting the white matter.

UR - http://www.scopus.com/inward/record.url?scp=77954746344&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77954746344&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.2295-10.2010

DO - 10.1523/JNEUROSCI.2295-10.2010

M3 - Article

VL - 30

SP - 9621

EP - 9630

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 28

ER -