Dexamethasone regulation of matrix metalloproteinase expression in CNS vascular endothelium.
Matrix metalloproteinases (MMPs) have been implicated in the early breakdown of the blood-brain barrier in neuroinflammatory disease. Although expression of these enzymes by resident glial cells and recruited immune cells has been described, altered expression of MMPs by the CNS vascular endothelial cells may also contribute to barrier disruption. In the present study, the in vitro expression of MMP-2 and -9 as well as tissue inhibitor of metalloproteinase (TIMP)-2 by rat CNS microvascular endothelial cells has been determined and compared with that by endothelial cell lines derived from rat aorta and high endothelial venules. Primary cultures of rat brain microvascular endothelial cells as well as the rat brain (GP8/3.9) and rat retinal endothelial (JG2/1) cell lines constitutively expressed MMP-2, -9 and TIMP-2. In vitro activation of CNS endothelium with the pro-inflammatory cytokines, tumour necrosis factor-alpha and interleukin-1beta, resulted in selective upregulation of MMP-9 activity, whereas no significant changes were seen in MMP-2 or TIMP-2 levels at 24 h. The addition of dexamethasone partially inhibited the cytokine-induced upregulation of MMP-9. Treatment of GP8/3.9 brain endothelial cells with active MMP-9 caused subtle but distinct alterations in the expression of the junctional protein, ZO-1. Quantitative differences found between CNS and non-CNS endothelial cells in the expression of both MMP-2 and -9, and in the expression of TIMP-2 demonstrate that CNS vascular endothelium is functionally distinct from non-CNS endothelium. These results suggest that cytokine-induced upregulation of MMP-9 expression by the CNS vascular endothelium may play a role in the pathogenesis of blood-brain and blood-retinal barrier breakdown in vivo.
Harkness
K A
KA
Division of Biomedical Science, Sheffield Hallam University, Department of Neurology, Royal Hallamshire Hospital, Sheffield, UK.
Adamson
P
P
Sussman
J D
JD
Davies-Jones
G A
GA
Greenwood
J
J
Woodroofe
M N
MN
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation / Q000187:drug effects* / Q000502:physiology*; D016207:Cytokines / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9 / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D062826:Zonula Occludens-1 Protein
D016207:Cytokines; D005938:Glucocorticoids; D008565:Membrane Proteins; D010750:Phosphoproteins; C569044:Tjp1 protein, rat; D062826:Zonula Occludens-1 Protein; D019716:Tissue Inhibitor of Metalloproteinase-2; D003907:Dexamethasone; D020782:Matrix Metalloproteinases; D020780:Matrix Metalloproteinase 9