The Mechanism of Excessive Intestinal Inflammation in Necrotizing Enterocolitis: An Immature Innate Immune Response

被引:260
作者
Nanthakumar, Nanda [1 ]
Meng, Di [1 ]
Goldstein, Allan M. [2 ]
Zhu, Weishu [1 ]
Lu, Lei [1 ]
Uauy, Ricardo [3 ]
Llanos, Adolfo [3 ]
Claud, Erika C. [4 ]
Walker, W. Allan [1 ]
机构
[1] Harvard Univ, Sch Med, Dev Gastroenterol Lab, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Pediat Surg Res Lab, MassGen Hosp Children, Boston, MA USA
[3] Univ Chile, Inst Nutr & Food Technol, Santiago, Chile
[4] Univ Chicago, Dept Pediat & Med, Sect Neonatol, Chicago, IL 60637 USA
基金
美国国家卫生研究院;
关键词
EPITHELIAL-CELLS; ENDOTOXIN TOLERANCE; BACTERIAL LIGANDS; UP-REGULATION; CORTICOSTEROIDS; ENTEROCYTES; EXPRESSION;
D O I
10.1371/journal.pone.0017776
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 NF kappa B1) 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, NFkB1 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.
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页数:8
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