Interleukin-6 modulation of intestinal epithelial tight junction permeability is mediated by JNK pathway activation of claudin-2 gene.
Interleukin-6 modulation of intestinal epithelial tight junction permeability is mediated by JNK pathway activation of claudin-2 gene.
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DOI：
10.1371/journal.pone.0085345
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Ma TY
中科院分区：
文献类型：
--
作者：
Al-Sadi R;Ye D;Boivin M;Guo S;Hashimi M;Ereifej L;Ma TY
肠上皮细胞紧密连接（TJ）屏障缺陷已被证明是肠道炎症发展的致病因素。白细胞介素-6（IL-6）是一种多效性促炎细胞因子，在促进肠道和体循环中的炎症反应中起重要作用。尽管IL-6在介导多种炎症反应中起着关键作用，但其对肠上皮屏障的影响尚不清楚。本研究的目的是研究IL-6对肠上皮TJ屏障的影响，并使用体外（过滤生长的Caco-2单层）和体内模型（小鼠肠灌注）系统来描述所涉及的细胞内机制。我们的结果表明IL-6导致Caco-2肠上皮TJ渗透性的位点选择性增加，导致分子半径<4 μ m的小分子通量增加。Caco-2 TJ渗透性的大小选择性增加受claudin-2表达的蛋白特异性增加的调节。IL-6增加TJ通透性需要激活JNK信号级联。AP-1的JNK途径激活导致AP-1结合到其在claudin-2启动子区域上的结合序列，导致启动子激活和随后的claudin-2基因转录和蛋白质合成以及TJ渗透性的增加。我们的体内小鼠灌注显示，IL-6对小鼠肠通透性的调节也由AP-1依赖性的claudin-2表达增加介导。总之，我们的研究首次表明，IL-6调节肠道TJ通透性的JNK激活AP-1和AP-1激活claudin-2基因的调节。
Defective intestinal epithelial tight junction (TJ) barrier has been shown to be a pathogenic factor in the development of intestinal inflammation. Interleukin-6 (IL-6) is a pleiotropic, pro-inflammatory cytokine which plays an important role in promoting inflammatory response in the gut and in the systemic circulation. Despite its key role in mediating variety inflammatory response, the effect of IL-6 on intestinal epithelial barrier remains unclear. The purpose of this study was to investigate the effect of IL-6 on intestinal epithelial TJ barrier and to delineate the intracellular mechanisms involved using in-vitro (filter-grown Caco-2 monolayers) and in-vivo model (mouse intestinal perfusion) systems. Our results indicated that IL-6 causes a site-selective increase in Caco-2 intestinal epithelia TJ permeability, causing an increase in flux of small-sized molecules having molecular radius <4 Å. The size-selective increase in Caco-2 TJ permeability was regulated by protein-specific increase in claudin-2 expression. The IL-6 increase in TJ permeability required activation of JNK signaling cascade. The JNK pathway activation of AP-1 resulted in AP-1 binding to its binding sequence on the claudin-2 promoter region, leading to promoter activation and subsequent increase in claudin-2 gene transcription and protein synthesis and TJ permeability. Our in-vivo mouse perfusion showed that IL-6 modulation of mouse intestinal permeability was also mediated by AP-1 dependent increase in claudin-2 expression. In conclusion, our studies show for the first time that the IL-6 modulation of intestinal TJ permeability was regulated by JNK activation of AP-1 and AP-1 activation of claudin-2 gene.
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影响因子：
6.3
作者：
Ito, H
通讯作者：
Ito, H
DOI：
10.1152/ajpgi.2000.279.5.g875
发表时间：
2000-11-01
影响因子：
4.5
作者：
Ma, TY;Hoa, NT;Merryfield, M
通讯作者：
Merryfield, M
影响因子：
5.7
作者：
Mazzon, E;Puzzolo, D;Cuzzocrea, S
通讯作者：
Cuzzocrea, S
DOI：
10.1097/00005373-199112000-00017
发表时间：
1991-12-01
影响因子：
--
作者：
SCHLUTER, B;KONIG, B;KONIG, W
通讯作者：
KONIG, W
DOI：
10.1006/clin.1998.4600
发表时间：
1998-12-01
期刊：
CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY
影响因子：
--
作者：
Rollwagen, FM;Yu, ZY;Pacheco, ND
通讯作者：
Pacheco, ND