Matrix Metalloproteinase-9 (MMP-9) induced disruption of intestinal epithelial tight junction barrier is mediated by NF-κB activation.
Matrix Metalloproteinase-9 (MMP-9) induced disruption of intestinal epithelial tight junction barrier is mediated by NF-κB activation.
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DOI：
10.1371/journal.pone.0249544
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发表时间：
2021
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;Engers J;Haque M;King S;Al-Omari D;Ma TY
基质金属蛋白酶-9(MMP9)在炎症性肠病(IBD)的炎症和组织损伤中起关键作用。在IBD患者中，以肠道通透性增加为特征的肠道紧密连接(TJ)屏障受损。炎症性肠病患者肠组织、血清和粪便中的基质金属蛋白酶-9水平升高。本实验室以往的研究表明，基质金属蛋白酶-9可引起肠上皮细胞通透性增加，而基质金属蛋白酶-9诱导的肠通透性增加是IBD肠炎症发生发展的重要致病因素。然而，基质金属蛋白酶-9调节肠屏障功能的细胞内机制尚不清楚。本研究的主要目的是以Caco-2单层作为体外模型系统，进一步阐明基质金属蛋白酶-9诱导肠上皮细胞通透性增加的分子机制。MMP9诱导的Caco-2TJ通透性增加与NF-κB p65的活化和胞核转位有关。通过小干扰RNA表达下调NF-κB p65，可抑制MMP9诱导的NF-κB靶基因IL-8、肌球蛋白轻链激酶蛋白的表达，从而阻止CaCO-2TJ通透性的增加。此外，基质金属蛋白酶-9对Caco-2肠上皮细胞TJ屏障功能的影响不是通过细胞凋亡或坏死来实现的。我们的研究结果表明，基质金属蛋白酶-9诱导的Caco-2肠上皮细胞TJ屏障功能的破坏是由核因子-κB通路激活MLCK调节的。
Matrix Metalloproteinase-9 (MMP-9) has been shown to play a key role in mediating inflammation and tissue damage in inflammatory bowel disease (IBD). In patients with IBD, the intestinal tight junction (TJ) barrier is compromised as characterized by an increase in intestinal permeability. MMP-9 is elevated in intestinal tissue, serum and stool of patients with IBD. Previous studies from our laboratory showed that MMP-9 causes an increase in intestinal epithelial TJ permeability and that the MMP-9 induced increase in intestinal permeability is an important pathogenic factor contributing to the development of intestinal inflammation in IBD. However, the intracellular mechanisms that mediate the MMP-9 modulation of intestinal barrier function remain unclear. The main aim of this study was to further elucidate the molecular mechanisms involved in MMP-9 induced increase in intestinal epithelial TJ permeability using Caco-2 monolayers as an in-vitro model system. MMP-9 induced increase in Caco-2 TJ permeability was associated with activation and cytoplasmic-to-nuclear translocation of NF-κB p65. Knocking-down NF-κB p65 by siRNA transfection prevented the MMP-9 induced expression of the NF-κB target gene IL-8, myosin light chain kinase (MLCK) protein expression, and subsequently prevented the increase in Caco-2 TJ permeability. In addition, the effect of MMP-9 on Caco-2 intestinal epithelial TJ barrier function was not mediated by apoptosis or necrosis. Our data show that the MMP-9 induced disruption of Caco-2 intestinal epithelial TJ barrier function is regulated by NF-κB pathway activation of MLCK.
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