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

Abstract

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 posttraumatic 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 factorMethylprednisolone (MP), a synthetic glucocorticoid (GC), is the only therapeutic agent approved by the Food and Drug Administration (FDA) for the treatment of acute traumatic spinal cord injury (SCI) in humans (Bracken, 1990). However, the effect of MP in SCI is modest (Nesathurai, 1998), and its mechanism of action remains to be fully delineated. GCs including MP are anti-inflammatory agents with a wide range of useful clinical applications (Barnes, 1998). A post-traumatic inflammatory reaction has been extensively documented in animal SCI models

Medicinal chemistry and pharmacology of genus Tripterygium (Celastraceae)

“…Activation of NF-κB and AP-1 is inhibited by activated glucocorticoid receptor (aGR), which is a glucocorticoid-receptor complex that functions as a transcription factor (Xu et al, 2001). Both an extract and 1 inhibited aGR-mediated gene activation .…”

Post-traumatic inflammation following spinal cord injury

“…106 Methylprednisolone has been shown to suppress the expression of MMP-9 after SCI. 107 Further, MMP released by axonal growth cones break down inhibitory CSPs. 35 Whether or not inflammation is beneficial or deleterious depends not only on the cellular and soluble components but also, importantly, on the timing of the acute inflammatory process.…”

Tumor Necrosis Factor Receptor Deletion Reduces Nuclear Factor-κB Activation, Cellular Inhibitor of Apoptosis Protein 2 Expression, and Functional Recovery after Traumatic Spinal Cord Injury

“…The NF-B heterodimer p50/RelA is known to upregulate various inflammatory mediator genes such as inducible nitric oxide synthase (iNOS), cytokines, cellular adhesive molecules, and proteases, which may be detrimental by perpetuating and intensifying an inflammatory reaction (Shimizu et al, 1990;Ledebur and Parks, 1995;Baldwin, 1996;Barnes, 1997;Barnes and Karin, 1997;O'Neill and Kaltschmidt, 1997;Schmedtje et al, 1997;Ghosh, 1999;Xu et al, 2001b). However, NF-B also may exert a cytoprotective role (Beg and Baltimore, 1996;Grilli et al, 1996;Van Antwerp et al, 1996).…”