Interferon (IFN)-฿1a and IFN-฿1b block IFN-?-Induced disintegration of endothelial junction integrity and barrier

A Minagar, A Long, T Ma, TH Jackson, RE Kelley… - Endothelium, 2003 - Taylor & Francis
A Minagar, A Long, T Ma, TH Jackson, RE Kelley, DV Ostanin, M Sasaki, AC Warren…
Endothelium, 2003Taylor & Francis
Recent clinical trials indicate the efficacy of interferon (IFN)-β1b in reducing relapse rate in
relapsing-remitting multiple sclerosis (MS), whereas a surge of IFN-γ 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-γ. However, the molecular mechanisms
underlying the beneficial effects of IFN-β1b against the deleterious effects of IFN-γ on the …
Recent clinical trials indicate the efficacy of interferon (IFN)-β1b in reducing relapse rate in relapsing-remitting multiple sclerosis (MS), whereas a surge of IFN-γ 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-γ. However, the molecular mechanisms underlying the beneficial effects of IFN-β1b against the deleterious effects of IFN-γ on the barrier formed by the junctional proteins remain to be characterized. The authors investigated the effects of IFN-β1b, IFN-β1a, and IFN-γ 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-β1b, IFN-β1a, IFN-γ, IFN-β1b plus IFN-γ, or IFN-β1a plus IFN-γ. IFN-β1b, IFN-β1a, and IFN-γ effects on occludin and VE-cadherin integrity and electrical resistance were assessed by Western blotting and immunofluorescence. IFN-γ 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-γ. IFN-β1b significantly attenuated the IFN-γ-induced decrease in occludin and VE-cadherin expression. The protective effects of IFN-β1a on IFN-γ-treated endothelial cells were similar to those of IFN-β1b. IFN-γ also significantly reduced endothelial monolayer electrical resistance; this effect was blocked by either IFN-β1a or IFN-β1b. IFN-β1a and IFN-β1b effectively prevent the IFN-γ-induced disintegration of the endothelial tight junctions and sustain barrier against the effects of IFN-γ. The protective effects of IFN-β on occludin and VE-cadherin stability appear to represent molecular mechanisms for the therapeutic effects of the IFN-β on blood brain barrier in MS.
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