title: Interferon (IFN)-beta 1a and IFN-beta 1b block IFN-gamma-induced disintegration of endothelial junction integrity and barrier.
abstract: Recent clinical trials indicate the efficacy of interferon (IFN)-beta 1b in reducing relapse rate in relapsing-remitting multiple sclerosis (MS), whereas a surge of IFN-gamma precedes and provokes acute relapses. Disruption of the cerebral endothelial barrier and transendothelial migration of inflammatory cell migration into the brain play a significant role in pathogenesis of MS and may be driven by this surge in IFN-gamma. However, the molecular mechanisms underlying the beneficial effects of IFN-beta 1b against the deleterious effects of IFN-gamma on the barrier formed by the junctional proteins remain to be characterized. The authors investigated the effects of IFN-beta 1b, IFN-beta 1a, and IFN-gamma on the integrity of two endothelial junctional proteins, occludin and vascular endothelial-cadherin (VE-cadherin). Human umbilical vein endothelial cell (HUVEC) layers were treated with IFN-beta 1b, IFN-beta 1a, IFN-gamma, IFN-beta 1b plus IFN-gamma, or IFN-beta 1a plus IFN-gamma. IFN-beta 1b, IFN-beta 1a, and IFN-gamma effects on occludin and VE-cadherin integrity and electrical resistance were assessed by Western blotting and immunofluorescence. IFN-gamma significantly reduced occludin expression and produced gaps in endothelial monolayers. VE-cadherin expression was decreased to a lesser extent in endothelial cells exposed to IFN-gamma. IFN-beta 1b significantly attenuated the IFN-gamma-induced decrease in occludin and VE-cadherin expression. The protective effects of IFN-beta 1a on IFN-gamma-treated endothelial cells were similar to those of IFN-beta 1b. IFN-gamma also significantly reduced endothelial monolayer electrical resistance; this effect was blocked by either IFN-beta 1a or IFN-beta 1b. IFN-beta 1a and IFN-beta 1b effectively prevent the IFN-gamma-induced disintegration of the endothelial tight junctions and sustain barrier against the effects of IFN-gamma. The protective effects of IFN-beta on occludin and VE-cadherin stability appear to represent molecular mechanisms for the therapeutic effects of the IFN-beta on blood brain barrier in MS.
authors.affiliation: Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130, USA.
authors.forename: A
authors.initials: A
authors.lastname: Minagar
authors.forename: A
authors.initials: A
authors.lastname: Long
authors.forename: T
authors.initials: T
authors.lastname: Ma
authors.forename: T H
authors.initials: TH
authors.lastname: Jackson
authors.forename: R E
authors.initials: RE
authors.lastname: Kelley
authors.forename: D V
authors.initials: DV
authors.lastname: Ostanin
authors.forename: M
authors.initials: M
authors.lastname: Sasaki
authors.forename: A C
authors.initials: AC
authors.lastname: Warren
authors.forename: A
authors.initials: A
authors.lastname: Jawahar
authors.forename: B
authors.initials: B
authors.lastname: Cappell
authors.forename: J S
authors.initials: JS
authors.lastname: Alexander
mesh_terms: D015703:Antigens, CD; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D015153:Blotting, Western; D015820:Cadherins / Q000187:drug effects / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D017097:Electric Impedance; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D007365:Intercellular Junctions / Q000187:drug effects / Q000378:metabolism*; D016899:Interferon-beta / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D062793:Occludin; D014471:Umbilical Veins / Q000166:cytology; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D016899:Interferon-beta; D007371:Interferon-gamma; D008565:Membrane Proteins; D062793:Occludin; D000099152:Cadherin 5; C568985:OCLN protein, human