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

Post-traumatic inflammatory reaction may contribute to progressive tissue d amage after spinal cord injury (SCI). Two key transcription factors, nuclea r factor kappaB (NF-kappaB) and activator protein-1 (AP-1), are activated i n inflammation. An increase in NF-kappaB binding activity has been shown in the injured spinal cord. We report activation of AP-1 after SCI. Electroph oretic mobility shift assay showed that AP-1 binding activity increased aft er 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 SC I. MP reduced posttraumatic AP-1 activation. RU486, a glucocorticoid recept or (GR) antagonist, reversed MP inhibition of AP-1 activation. Immunostaini ng showed an increase in the expression of the Fos-B and c-Jun components o f AP-1 in the injured cord. A c-fos antisense oligodeoxynucleotide (ODN) in hibited AP-1, but lnot 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 afte r SCI. RU486 reversed this MP effect. The c-fos antisense ODN, however, fai led 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 o f inflammatory genes such as MMP-1 and MMP-9 that are transactivated jointl y by AP-1 and NF-kappaB may not be suppressed by inhibiting only AP-1 activ ity.