The mechanism of excessive intestinal inflammation in necrotizing enterocolitis: an immature innate immune response.
The mechanism of excessive intestinal inflammation in necrotizing enterocolitis: an immature innate immune response.
复制标题
DOI：
10.1371/journal.pone.0017776
复制
发表时间：
2011-03-21
期刊：
影响因子：
3.7
通讯作者：
Walker WA
中科院分区：
文献类型：
--
作者：
Nanthakumar N;Meng D;Goldstein AM;Zhu W;Lu L;Uauy R;Llanos A;Claud EC;Walker WA
坏死性小肠结肠炎（NEC）是一种严重的新生儿肠道炎症性疾病，主要发生在早产儿中，可导致显著的发病率和死亡率。NEC的发病机制与过度的炎症性IL-8反应有关。在这项研究中，我们假设这种过度的炎症反应与先天免疫反应基因的不成熟表达有关。为了解决这一假设，先天性免疫应答基因的肠RNA表达分析是在对来自胎儿、NEC患者和儿童的切除回肠上皮进行激光捕获显微切割后进行的，并在离体人肠异种移植物中得到证实。通过qRT-PCR表征toll样受体（TLR）-2和-4、其信号分子和转录因子（MyD 88、TRAF-6和NFκB1）以及负调节因子（SIGIRR、IRAK-M、A-20和TOLLIP）和效应因子IL-8的mRNA水平变化。与成熟人肠细胞相比，胎儿肠细胞中TLR 2、TLR 4、MyD 88、TRAF-6、NFκB1和IL-8 mRNA的表达增加，而SIGIRR、IRAK-M、A-20和TOLLIP mRNA的表达减少，并且在NEC肠细胞中进一步改变。在未成熟但不成熟的人肠异种移植物中观察到mRNA表达的类似变化。基因表达的确认也验证了选择性蛋白质测量和建议的证据表明，未成熟的TRL 4肠上皮细胞表面表达的内化在成熟的肠上皮细胞。可的松，一种肠成熟因子，治疗仅纠正了未成熟肠异种移植物中的mRNA差异。使用特异性siRNA来减弱原代胎儿肠上皮细胞培养物的表达，TOLLIP和A-20都被证实在通过表现出在NEC肠中观察到的相同的过度炎症反应而被敲低时是重要的。我们的结论是，过度的炎症反应的不成熟的肠道，NEC的一个标志，是由于先天免疫反应基因的发育不成熟。
Necrotizing enterocolitis (NEC) is a devastating neonatal intestinal inflammatory disease, occurring primarily in premature infants, causing significant morbidity and mortality. The pathogenesis of NEC is associated with an excessive inflammatory IL-8 response. In this study, we hypothesized that this excessive inflammatory response is related to an immature expression of innate immune response genes. To address this hypothesis, intestinal RNA expression analysis of innate immune response genes was performed after laser capture microdissection of resected ileal epithelium from fetuses, NEC patients and children and confirmed in ex vivo human intestinal xenografts. Changes in mRNA levels of toll-like receptors (TLR)-2 and -4, their signaling molecules and transcription factors (MyD88, TRAF-6 and NFκB1) and negative regulators (SIGIRR, IRAK-M, A-20 and TOLLIP) and the effector IL-8 were characterized by qRT-PCR. The expression of TLR2, TLR4, MyD88, TRAF-6, NFκB1 and IL-8 mRNA was increased while SIGIRR, IRAK-M, A-20 and TOLLIP mRNA were decreased in fetal vs. mature human enterocytes and further altered in NEC enterocytes. Similar changes in mRNA expression were observed in immature, but not mature, human intestinal xenografts. Confirmation of gene expression was also validated with selective protein measurements and with suggested evidence that immature TRL4 enterocyte surface expression was internalized in mature enterocytes. Cortisone, an intestinal maturation factor, treatment corrected the mRNA differences only in the immature intestinal xenograft. Using specific siRNA to attenuate expression of primary fetal enterocyte cultures, both TOLLIP and A-20 were confirmed to be important when knocked down by exhibiting the same excessive inflammatory response seen in the NEC intestine. We conclude that the excessive inflammatory response of the immature intestine, a hallmark of NEC, is due to a developmental immaturity in innate immune response genes.
登录
查看更多内容
DOI：
10.1152/ajpgi.00169.2004
发表时间：
2005-01-01
影响因子：
4.5
作者：
Nanthakumar, NN;Young, C;Walker, WA
通讯作者：
Walker, WA
影响因子：
5.3
作者：
Ohnuma, K;Yamochi, T;Morimoto, C
通讯作者：
Morimoto, C
DOI：
10.1073/pnas.0401710101
发表时间：
2004-05-11
影响因子：
11.1
作者：
Claud, EC;Lu, L;Cherayil, BJ
通讯作者：
Cherayil, BJ
影响因子：
32.4
作者：
Xiao, Hui;Gulen, Muhammet Fatih;Li, Xiaoxia
通讯作者：
Li, Xiaoxia
影响因子：
4.8
作者：
Claud, EC;Walker, WA
通讯作者：
Walker, WA