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The Journal of Neuroscience, January 1, 2001, 21(1):92-97

Glucocorticoid Receptor-Mediated Suppression of Activator Protein-1 Activation and Matrix Metalloproteinase Expression after Spinal Cord Injury

Jan Xu¹, Gyeong-Moon Kim¹, S. Hinan Ahmed¹, Jinming Xu¹, Ping Yan², Xiao Ming Xu², and Chung Y. Hsu¹

¹ Department of Neurology and Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri 63110, and ² Department of Anatomy and Neurobiology, Saint Louis University School of Medicine, St. Louis, Missouri 63104

Post-traumatic inflammatory reaction may contribute to progressive tissue damage after spinal cord injury (SCI). Two key transcription factors, nuclear factor B (NF-B) and activator protein-1 (AP-1), are activated in inflammation. An increase in NF-B 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-B, activation after SCI. AP-1 and NF-B 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-B 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-B may not be suppressed by inhibiting only AP-1 activity.

Key words: inflammation; methylprednisolone; NF-B; protease; RU486; transcription factor

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21192-06$05.00/0

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