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Received January 25, 2007
Revised February 12, 2007
Accepted after revision February 16, 2007
1 University of Wurzburg
2 JW Goethe University Frankfurt
3 Georg-August-Universität Göttingen
4 Julius-Maximilians-University
* To whom correspondence should be addressed. E-mail: carola.foerster{at}mail.uni-wuerzburg.de.
In many neuroinflammatory conditions, including multiple sclerosis (MS), encephalitis, meningitis, brain tumors and cerebral ischemia, the matrix metalloproteinases (MMP) play an important role in disrupting the blood-brain barrier (BBB). Normally under tight regulation, increased MMP-9 cerebrospinal fluid levels and excessive proteolytic activity is detected in the blood and cerebrospinal fluid in patients with acute MS. MMP-9 is a member of the type IV collagenases, which attack components of the endothelial basal lamina, including type IV collagen. The disruption of the BBB and clinical symptoms can be reduced with different inhibitors to MMPs including activators of tissue inhibitor of metalloproteinases-1 (TIMP-1), the cognate tissue inhibitor of MMP-9. Since intravenous glucocorticoid (GC) treatment reduces the levels of MMP-9 markedly in patients, we hypothesised that GC effects might be mediated by transcriptional activation of the TIMP-1 gene in addition to reported repressive effects on MMP-9 transcription. Our results provide direct evidence that GC increase TIMP-1 in the brain endothelial cell line cEND, prevent alterations in microvascular integrin-alpha1 subunit expression and help maintain endothelial barrier function in response to pro-inflammatory stimuli (TNF administration). GC-induced upregulation of TIMP-1 expression by the CNS vascular endothelium may thus play a role in preservation of the endothelial basal lamina and maintain integrin 1 expression important for vessel wall integrity.
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