Dexamethasone induces the expression of metalloproteinase inhibitor TIMP-1 in the murine cerebral vascular endothelial cell line cEND.
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 alpha1 subunit expression and help maintain endothelial barrier function in response to pro-inflammatory stimuli (TNFalpha 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 alpha1 and tight junction protein expression important for vessel wall integrity.
Förster
Carola
C
Institute of Anatomy and Cell Biology, University of Würzburg, Koellikerstrasse 6, D-97070 Würzburg, Germany. carola.foerster@mail.uni-wuerzburg.de
Kahles
Timo
T
Kietz
Silke
S
Drenckhahn
Detlev
D
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000098:blood supply*; D002196:Capillaries / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D024141:Collagen Type IV / Q000037:antagonists & inhibitors; D003907:Dexamethasone / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D039423:Integrin alpha1 / Q000378:metabolism; D039564:Integrin alphaV / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D011401:Promoter Regions, Genetic / Q000187:drug effects; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D024141:Collagen Type IV; D005938:Glucocorticoids; D039423:Integrin alpha1; D039564:Integrin alphaV; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D020780:Matrix Metalloproteinase 9