Glucocorticoid receptor-mediated suppression of activator protein-1 activation and matrix metalloproteinase expression after spinal cord injury

Jan Xu, Gyeong Moon Kim, S. Hinan Ahmed, Jinming Xu, Ping Yan, Xiao Ming Xu, Chung Y. Hsu

Research output: Contribution to journalArticlepeer-review

93 Scopus citations

Abstract

Post-traumatic inflammatory reaction may contribute to progressive tissue damage after spinal cord injury (SCI). Two key transcription factors, nuclear factor κB (NF-κB) and activator protein-1 (AP-1), are activated in inflammation. An increase in NF-κB binding activity has been shown in the injured spinal cord. We report activation of AP-1 after SCI. Electrophoretic mobility shift assay showed that AP-1 binding activity increased after SCI, starting at 1 hr, peaking at 8 hr, and declining to basal levels by 7 d. Methylprednisolone (MP) is the only therapeutic agent approved by the Food and Drug Administration for treating patients with acute traumatic SCI. MP reduced post-traumatic AP-1 activation. RU486, a glucocorticoid receptor (GR) antagonist, reversed MP inhibition of AP-1 activation. Immunostaining showed an increase in the expression of the Fos-B and c-Jun components of AP-1 in the injured cord. A c-fos antisense oligodeoxynucleotide (ODN) inhibited AP-1, but not NF-κB, activation after SCI. AP-1 and NF-κB can transactivate genes encoding matrix metalloproteinase-1 (MMP-1) and MMP-9. Western blotting and immunostaining show increased expression of MMP-1 and MMP-9 in the injured cord. MP inhibited MMP-1 and MMP-9 expression after SCI. RU486 reversed this MP effect. The c-fos antisense ODN, however, failed to suppress MMP-1 or MMP-9 expression. These findings demonstrate that MP may suppress post-traumatic inflammatory reaction by inhibiting both the AP-1 and NF-κB transcription cascades via a GR mechanism. Expression of inflammatory genes such as MMP-1 and MMP-9 that are transactivated jointly by AP-1 and NF-κB may not be suppressed by inhibiting only AP-1 activity.

Original languageEnglish (US)
Pages (from-to)92-97
Number of pages6
JournalJournal of Neuroscience
Volume21
Issue number1
DOIs
StatePublished - Jan 1 2001

Keywords

  • Inflammation
  • Methylprednisolone
  • NF-κB
  • Protease
  • RU486
  • Transc ription factor

ASJC Scopus subject areas

  • Neuroscience(all)

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