TNF-α Modulation of Intestinal Epithelial Tight Junction Barrier Is Regulated by ERK1/2 Activation of Elk-1
TNF-α Modulation of Intestinal Epithelial Tight Junction Barrier Is Regulated by ERK1/2 Activation of Elk-1
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DOI：
10.1016/j.ajpath.2013.09.001
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发表时间：
2013-12-01
影响因子：
6
通讯作者：
Ma, Thomas Y.
中科院分区：
文献类型：
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作者：
Al-Sadi, Rana;Guo, Shuhong;Ma, Thomas Y.
肿瘤坏死因子（TNF -α）是一种促炎细胞因子，在炎症性肠病的发病机制中起着关键作用。TNF -α会导致肠道通透性增加；然而，所涉及的信号通路和分子机制仍不清楚。本研究的主要目的是探究丝裂原活化蛋白激酶通路（ERK1/2和p38激酶）的作用以及所涉及的分子过程。采用由Caco - 2单层细胞构成的体外肠道上皮模型系统以及体内小鼠模型系统来阐明TNF -α对紧密连接屏障影响所涉及的细胞和分子机制。TNF -α诱导的Caco - 2紧密连接通透性增加是由ERK1/2信号通路的激活介导的，而非p38激酶通路。ERK1/2通路的激活导致含ETS结构域的转录因子Elk - 1的磷酸化和激活。激活的Elk - 1转位到细胞核，在那里它与肌球蛋白轻链激酶（MLCK）启动子区域上的结合基序结合，导致MLCK启动子活性和基因转录的激活。此外，体内肠道灌注研究还表明，TNF -α诱导的小鼠肠道通透性增加需要ERK1/2依赖的Elk - 1激活。这些研究为调节TNF -α诱导的肠道上皮紧密连接通透性增加的细胞和分子过程提供了新的见解。
Tumor necrosis factor (TNF-alpha) is a proinflammatory cytokine that plays a critical role in the pathogenesis of inflammatory bowel disease. TNF-alpha causes an increase in intestinal permeability; however, the signaling pathways and the molecular mechanisms involved remain unclear. The major purpose of this study was to investigate the role of MAP kinase pathways (ERK1/2 and p38 kinase) and the molecular processes involved. An in vitro intestinal epithelial model system consisting of Caco-2 monolayers and an in vivo mouse model system were used to delineate the cellular and molecular mechanisms involved in TNF-alpha effects on tight junction barrier. The TNF-alpha-induced increase in Caco-2 tight junction permeability was mediated by activation of the ERK1/2 signaling pathway, but not the p38 kinase pathway. Activation of the ERK1/2 pathway led to phosphorylation and activation of the ETS domain-containing transcription factor Elk-1. The activated Elk-1 translocated to the nucleus, where it bound to its binding motif on the myosin Light chain k-inase (MLCK) promoter region, leading to the activation of MLCK promoter activity and gene transcription. In addition, in vivo intestinal perfusion studies also indicated that the TNF-alpha-induced increase in mouse intestinal permeability requires ERK1/2-dependent activation of Elk-1. These studies provide novel insight into the cellular and molecular processes that regulate the TNF-alpha-induced increase in intestinal epithetial tight junction permeability.