Minagar A, Long A, Ma T, Jackson TH, Kelley RE, Ostanin DV, Sasaki M, Warren AC, Jawahar A, Cappell B, Alexander JS.
Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA.
Recent clinical trials indicate the efficacy of interferon (IFN)-beta1b 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-beta1b 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-beta1b, IFN-beta1a, 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-beta1b, IFN-beta1a, IFN-gamma, IFN-beta1b plus IFN-gamma, or IFN-beta1a plus IFN-gamma.
IFN-beta1b, IFN-beta1a, 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-beta1b significantly attenuated the IFN-gamma-induced decrease in occludin and VE-cadherin expression.
The protective effects of IFN-beta1a on IFN-gamma-treated endothelial cells were similar to those of IFN-beta1b.
IFN-gamma also significantly reduced endothelial monolayer electrical resistance; this effect was blocked by either IFN-beta1a or IFN-beta1b.
IFN-beta1a and IFN-beta1b 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.