RT Journal Article
SR Electronic
T1 Glucocorticoid Receptor-Mediated Suppression of Activator Protein-1 Activation and Matrix Metalloproteinase Expression after Spinal Cord Injury
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 92
OP 97
DO 10.1523/JNEUROSCI.21-01-00092.2001
VO 21
IS 1
A1 Jan Xu
A1 Gyeong-Moon Kim
A1 S. Hinan Ahmed
A1 Jinming Xu
A1 Ping Yan
A1 Xiao Ming Xu
A1 Chung Y. Hsu
YR 2001
UL http://www.jneurosci.org/content/21/1/92.abstract
AB 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. Ac-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. Thec-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.