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CARDIOVASCULAR |
1 University of Würzburg, Institute of Anatomy and Cell Biology, Koellikerstrasse 6, D-97070 Würzburg, Germany
2 University Hospital Frankfurt, JW Goethe University, Department of Neurology, Schleusenweg 2-16, ZNN, D-60528 Frankfurt/Main, Germany
3 Georg-August-Universität Göttingen, Zentrum für Kinderheilkunde und Jugendmedizin, Abteilung Pädiatrie I, Robert-Koch-Strasse 40, 37075 Göttingen, Germany
In many neuroinflammatory conditions, including multiple sclerosis (MS), encephalitis, meningitis, brain tumours and cerebral ischaemia, the matrix metalloproteinases (MMPs) 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 hypothesized 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 GCs increase TIMP-1 in the brain endothelial cell line cEND, prevent alterations in microvascular integrin 
1 subunit expression and help maintain endothelial barrier function in response to pro-inflammatory stimuli (TNF administration). GC-induced up-regulation of TIMP-1 expression by the CNS vascular endo-thelium may thus play a role in preservation of the endothelial basal lamina and maintain integrin 1 and tight junction protein expression important for vessel wall integrity.
(Received 24 January 2007;
accepted after revision 18 February 2007;
first published online 22 February 2007)
Corresponding author C. Förster: Institute of Anatomy and Cell Biology, University of Würzburg, Koellikerstrasse 6, D-97070 Würzburg, Germany. Email: carola.foerster{at}mail.uni-wuerzburg.de
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