Glucocorticoid effects on endothelial barrier function in the murine brain endothelial cell line cEND incubated with sera from patients with multiple sclerosis.
Compromised blood-brain barrier integrity is a major hallmark of active multiple sclerosis (MS). Alterations in brain endothelial tight junction protein and gene expression occur early during neuroinflammation but there is little known about the underlying mechanisms. In this study, we analysed barrier compromising effects of sera from MS patients and barrier restoring effects of glucocorticoids on blood-brain barrier integrity in vitro. cEND murine brain microvascular endothelial cell monolayers were incubated with sera from patients in active phase of disease or in relapse. Data were compared with effects of the glucocorticoid dexamethasone alone or in combination with MS sera on barrier integrity. Tight junction protein levels and gene expression were evaluated concomitant with barrier integrity. We reveal downregulation of claudin-5 and occludin protein and mRNA and an accompanying upregulation in expression of matrix metalloproteinase MMP-9 after incubation with serum from active disease and remission and also a minor reconstitution of barrier functions related to dexamethasone treatment. Moreover, we for the first time describe downregulation of claudin-5 and occludin protein after incubation of cEND cells with sera from patients in remission phase of MS. Our findings reveal direct and differential effects of MS sera on blood-brain barrier integrity.
Blecharz
Kinga G
KG
Department of Anaesthesiology and Critical Care, University of Würzburg, 97080 Würzburg, Germany.
Haghikia
Aiden
A
Stasiolek
Mariusz
M
Kruse
Niels
N
Drenckhahn
Detlev
D
Gold
Ralf
R
Roewer
Norbert
N
Chan
Andrew
A
Förster
Carola Y
CY
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D001921:Brain / Q000098:blood supply*; D002199:Capillary Permeability / Q000187:drug effects*; D002460:Cell Line; D062507:Claudin-5; D016207:Cytokines / Q000097:blood; D003907:Dexamethasone / Q000494:pharmacology*; D015536:Down-Regulation; D017097:Electric Impedance; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000097:blood* / Q000276:immunology; D062793:Occludin; D012333:RNA, Messenger / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism
D062507:Claudin-5; C491511:Cldn5 protein, mouse; D016207:Cytokines; D005938:Glucocorticoids; D018836:Inflammation Mediators; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse; D012333:RNA, Messenger; D003907:Dexamethasone; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse