白细胞介素-1β介导β-连环蛋白驱动的Caco2细胞中Claudin-3下调及屏障功能障碍。
Interleukin-1β Mediates β-Catenin-Driven Downregulation of Claudin-3 and Barrier Dysfunction in Caco2 Cells.
作者信息
Haines R J, Beard R S, Chen L, Eitnier R A, Wu M H
机构信息
Department of Surgery, University of South Florida, Morsani College of Medicine, 12901 Bruce B. Downs Blvd., MDC 8, Office MDC 2012, Tampa, FL, 33612, USA.
James A. Haley Veterans' Hospital, Tampa, FL, USA.
出版信息
Dig Dis Sci. 2016 Aug;61(8):2252-2261. doi: 10.1007/s10620-016-4145-y. Epub 2016 Apr 13.
BACKGROUND
IL-1β is a cytokine involved in mediating epithelial barrier dysfunction in the gut. It is known that IL-1β mediates activation of non-muscle myosin light chain kinase in epithelial cells, but the precise mechanism by which epithelial barrier dysfunction is induced by IL-1β is not understood.
METHODS AND RESULTS
Using a Caco2 cell model, we show that the expression of the tight junction protein, claudin-3, is transcriptionally downregulated by IL-1β treatment. In addition, after assessing protein and mRNA expression, and protein localization, we show that inhibition of nmMLCK rescues IL-1β-mediated decrease in claudin-3 expression as well as junction protein redistribution. Using chromatin immunoprecipitation assays, we also show that β-catenin targeting of the claudin-3 promoter occurs as a consequence of IL-1β-mediated epithelial barrier dysfunction, and inhibition of nmMLCK interferes with this interaction.
CONCLUSIONS
Taken together, these data represent the first line of evidence demonstrating nmMLCK regulation of claudin-3 expression in response to IL-1β-treated epithelial cells.
背景
白细胞介素-1β（IL-1β）是一种参与介导肠道上皮屏障功能障碍的细胞因子。已知IL-1β介导上皮细胞中非肌肉型肌球蛋白轻链激酶的激活，但IL-1β诱导上皮屏障功能障碍的确切机制尚不清楚。
方法与结果
使用Caco2细胞模型，我们发现紧密连接蛋白claudin-3的表达在IL-1β处理后发生转录下调。此外，在评估蛋白质和mRNA表达以及蛋白质定位后，我们发现抑制非肌肉型肌球蛋白轻链激酶（nmMLCK）可挽救IL-1β介导的claudin-3表达降低以及连接蛋白重新分布。使用染色质免疫沉淀试验，我们还表明，由于IL-1β介导的上皮屏障功能障碍，β-连环蛋白靶向claudin-3启动子，而抑制nmMLCK会干扰这种相互作用。
结论
综上所述，这些数据代表了首个证据，证明nmMLCK对IL-1β处理的上皮细胞中claudin-3表达的调节作用。
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