Developmentally regulated IκB expression in intestinal epithelium and susceptibility to flagellin-induced inflammation
Developmentally regulated IκB expression in intestinal epithelium and susceptibility to flagellin-induced inflammation
复制标题
DOI：
10.1073/pnas.0401710101
复制
发表时间：
2004-05-11
影响因子：
11.1
通讯作者：
Cherayil, BJ
中科院分区：
文献类型：
--
作者：
Claud, EC;Lu, L;Cherayil, BJ
坏死性小肠结肠炎是一种破坏性的炎症性疾病，几乎只发生在早产儿中。虽然其确切的发病机制尚不清楚，但我们推测其可能是由于未成熟肠对微生物感染产生异常强烈和破坏性反应的倾向所致。为了支持这一观点，我们报道了IL-8对未成熟的人肠上皮细胞系细菌感染的反应显著高于成熟的肠上皮细胞系。两种细胞系的反应都是鞭毛蛋白依赖性的。与IL-8产生的差异相对应，与成熟肠细胞相比，未成熟肠细胞表达的特异性IkappaB基因水平明显较低。在原代大鼠肠上皮细胞中也观察到细胞因子反应和IkappaB表达的类似发育调节差异，表明这些观察结果不是细胞系的特异性。此外，当通过转染增加未成熟细胞系中IkappaB α的表达水平时，鞭毛蛋白依赖性IL-8反应就会减弱。因此，我们已经证明了一个以前未描述的发展调节IkappaB在肠道中的表达参与调节IL-8对细菌感染的反应，这可能有助于年龄特异性炎症性肠病，如坏死性小肠结肠炎的发病机制。
Necrotizing enterocolitis is a devastating inflammatory condition of the intestine that occurs almost exclusively in premature newborns. Although its exact pathogenesis is unclear, we have postulated that it may result from a predisposition of the immature intestine to mount an unusually robust and damaging response to microbial infection. In support of this idea, we report that the IL-8 response of an immature human enterocyte cell line to bacterial infection was significantly higher than that of a mature enterocyte cell line. The response in both cell lines was flagellin-dependent. Corresponding to the difference in IL-8 production, the immature enterocytes expressed appreciably lower levels of specific IkappaB genes when compared with the mature enterocytes. Similar developmentally regulated differences in cytokine response and IkappaB expression were also seen in primary rat enterocytes, indicating that these observations were not peculiarities of the cell lines. Furthermore, when the level of IkappaBalpha expression was increased in the immature cell line by transfection, the flagellin-dependent IL-8 response was attenuated. Thus, we have demonstrated a previously undescribed developmental regulation of IkappaB expression in the intestine involved in modulating the IL-8 response to bacterial infection, which may contribute to the pathogenesis of age-specific inflammatory bowel diseases such as necrotizing enterocolitis.