Xu, et al. (2001). Glucocorticoid receptor-mediated suppression of activator protein-1 activation and matrix metalloproteinase expression after spinal cord injury

[Wise Young]

Xu J, Kim GM, Ahmed SH, Yan P, Xu XM and Hsu CY (2001). Glucocorticoid receptor-mediated suppression of activator protein-1 activation and matrix metalloproteinase expression after spinal cord injury. J Neurosci. 21 (1): 92-7. Summary: Post-traumatic inflammatory reaction may contribute to progressive tissue damage after spinal cord injury (SCI). Two key transcription factors, nuclear factor kappaB (NF-kappaB) and activator protein-1 (AP- 1), are activated in inflammation. An increase in NF-kappaB 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-kappaB, activation after SCI. AP-1 and NF-kappaB 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-kappaB 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-kappaB may not be suppressed by inhibiting only AP-1 activity. <http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&dopt=r&uid=11150324
http://www.jneurosci.org/cgi/content/full/21/1/92
http://www.jneurosci.org/cgi/content/abstract/21/1/92> Department of Neurology and Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri 63110, USA.