title: Differential effects of hydrocortisone and TNFalpha on tight junction proteins in an in vitro model of the human blood-brain barrier.
abstract: Homeostasis of the central nervous system (CNS) microenvironment is maintained by the blood-brain barrier (BBB) which regulates the transport of molecules from blood into brain and back. Many disorders change the functionality and integrity of the BBB. Glucocorticoids are being used sucessfully in the treatment of some disorders while their effects on others are questionable. In addition, conflicting results between clinical and experimental experience using animal models has arisen, so that the results of molecular studies in animal models need to be revisited in an appropriate in vitro model of the human BBB for more effective treatment strategies. Using the human brain microvascular endothelial cell line hCMEC/D3, the influence of glucocorticoids on the expression of barrier constituting adherens junction and tight junction transmembrane proteins (VE-cadherin, occludin, claudins) was investigated and compared to other established BBB models. In hCMEC/D3 cells the administration of glucocorticoids induced expression of the targets occludin 2.75 +/- 0.04-fold and claudin-5 up to 2.32 +/- 0.11-fold, which is likely to contribute to the more than threefold enhancement of transendothelial electrical resistance reflecting barrier tightness. Our analyses further provide direct evidence that the GC hydrocortisone prevents endothelial barrier breakdown in response to pro-inflammatory stimuli (TNFalpha administration), which could be demonstrated to be partly based on maintenance of occludin levels. Our studies strongly suggest stabilization of BBB function as a mode of GC action on a molecular level in the human brain vasculature.
authors.affiliation: Institute of Anatomy and Cell Biology, University of Würzburg, Koellikerstrasse 6, D-97070 Würzburg, Germany. carola.foerster@mail.uni-wuerzburg.de
authors.forename: Carola
authors.initials: C
authors.lastname: Förster
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Burek
authors.forename: Ignacio A
authors.initials: IA
authors.lastname: Romero
authors.forename: Babette
authors.initials: B
authors.lastname: Weksler
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Couraud
authors.forename: Detlev
authors.initials: D
authors.lastname: Drenckhahn
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000502:physiology; D062445:Claudin-1; D062465:Claudin-3; D062507:Claudin-5; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism*; D008954:Models, Biological; D062793:Occludin; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014655:Vascular Resistance / Q000502:physiology; D000099152:Cadherin 5
chemical_list: D000893:Anti-Inflammatory Agents; D015703:Antigens, CD; D015820:Cadherins; D062445:Claudin-1; D062465:Claudin-3; D062507:Claudin-5; D006854:Hydrocortisone; D008565:Membrane Proteins; D062793:Occludin; D014409:Tumor Necrosis Factor-alpha; D000099152:Cadherin 5; C568108:CLDN1 protein, human; C568122:CLDN3 protein, human; C107466:CLDN5 protein, human; C568985:OCLN protein, human