Wise Young
10-01-2001, 11:52 PM
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
1Â*Department of Neurology and Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri 63110,Â*and 2Â*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-KB) and activator protein-1 (AP-1), are activated in inflammation. An increase in NF-KB 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 1Â*hr, peaking at 8Â*hr, and declining to basal levels by 7Â*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-KB, activation after SCI. AP-1 and NF-KB 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-KB 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-KB may not be suppressed by inhibiting only AP-1 activity.
Key words: inflammation; methylprednisolone; NF-KB; protease; RU486; transcription factor
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
1Â*Department of Neurology and Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri 63110,Â*and 2Â*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-KB) and activator protein-1 (AP-1), are activated in inflammation. An increase in NF-KB 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 1Â*hr, peaking at 8Â*hr, and declining to basal levels by 7Â*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-KB, activation after SCI. AP-1 and NF-KB 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-KB 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-KB may not be suppressed by inhibiting only AP-1 activity.
Key words: inflammation; methylprednisolone; NF-KB; protease; RU486; transcription factor