Interferon (IFN)-β1a and IFN-β1b block IFN-γ-induced disintegration of endothelial junction integrity and barrier
Interferon (IFN)-β1a and IFN-β1b block IFN-γ-induced disintegration of endothelial junction integrity and barrier
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DOI：
10.1080/10623320390272299
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发表时间：
2003-01-01
影响因子：
--
通讯作者：
Alexander, JS
中科院分区：
文献类型：
--
作者：
Minagar, A;Long, A;Alexander, JS
最近的临床试验表明干扰素（IFN）-β 1b在降低复发缓解型多发性硬化症（MS）复发率方面的疗效，而IFN-γ的激增先于并引发急性复发。脑内皮屏障的破坏和炎性细胞迁移到脑中的跨内皮迁移在MS的发病机制中起重要作用，并且可能由IFN-γ的这种激增驱动。然而，IFN-β 1b对IFN-γ对由连接蛋白形成的屏障的有害作用的有益作用的分子机制仍有待表征。作者研究了IFN-β 1b、IFN-β 1a和IFN-γ对两种内皮连接蛋白（occludin和vascular endothelial-cadherin，VE-钙粘蛋白）完整性的影响。用IFN-β 1b、IFN-β 1a、IFN-γ、IFN-β 1b + IFN-γ或IFN-β 1a + IFN-γ处理人脐静脉内皮细胞（HUVEC）层。IFN-β 1b，IFN-β 1a和IFN-γ对occludin和VE-钙粘蛋白完整性和电阻的影响通过Western印迹和免疫荧光进行了评估。IFN-γ显着降低occludin的表达，并在内皮细胞单层中产生间隙。在暴露于IFN-γ的内皮细胞中，VE-钙粘蛋白表达降低程度较小。IFN-β 1b显著减弱IFN-γ诱导的occludin和VE-钙粘蛋白表达降低。WN-β 1a对IFN-γ处理的内皮细胞的保护作用与IFN-β 1b相似。IFN-γ也显着降低内皮细胞单层电阻;这种效果被阻断的WN-β 1a或IFN-β 1b。IFN-β 1a和IFN-β 1b有效防止IFN-γ诱导的内皮紧密连接的崩解，并维持针对IFN-γ作用的屏障。IFN-β对闭合蛋白和VE-钙粘蛋白稳定性的保护作用似乎代表了IFN-β对MS血脑屏障治疗作用的分子机制。
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 WN-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 WN-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.