Gene expression in the model system of neonatal brain damage with increased levels of serum IL-18

我们发现脐带血IL-18是早产儿脑损伤继而脑瘫的生化标志物，脓毒症是导致新生儿脑损伤的另一个因素。我们研究了IL-18和内毒素LPS （toll样受体（TLR）配体之一）对人类未成熟内皮细胞的影响。cDNA微阵列分析显示，LPS诱导了几个趋化因子和受体基因以及子宫内膜出血相关因子基因Lefty-A的表达。IL-18对Lefty A的诱导作用在一个细胞系中表现为高度诱导，在另一个细胞系中表现为中度诱导。我们还使用了cd34阳性的人类毛囊来源的干细胞，这些干细胞可以分化为角质形成细胞和神经细胞。LPS诱导了Lefty A、IL8R和IL5RA的表达，IL-18增强了几种趋化因子的表达。通过其他TLR配体处理，可诱导chomokine家族和ICAM基因在一定水平上表达，但IL-18的表达水平在不同细胞株之间存在差异。最近，一些报道指出，DNA多态性改变了严重感染的临床表现。综上所述，在早产儿中，严重感染和高血清IL-18可能通过tlr介导的信号对未成熟细胞造成损伤，DNA多态性可能在改变对信号的敏感性中起重要作用。

We found that IL-18 in cord blood serves as a biochemical marker of brain damages followed by cerebral palsy in premature infants, and sepsis is another factor to induce neonatal brain damages. We examined the effects of IL-18 and endotoxin LPS, one of the toll-like receptor(TLR) ligands, to human immature endothelial cells. The cDNA microarray analysis showed that the expression of several chemokine and receptor genes and the endometrial bleeding associated factor gene, also known as Lefty-A, was induced by LPS. Lefty A was highly induced by IL-18 in one cell line but moderately in the other. We also used CD34-positive human hair follicle-derived stem cells that can differentiate to keratinocytes and neuronal cells. LPS induced the expression of Lefty A, IL8R and IL5RA, and IL-18 enhanced the expression of several chemokines. By treatment with other TLR ligands, the expression of the chomokine family and the ICAM genes were induced at a constant level, but the expression levels of IL-18 were variable among cell strains.Recently, several reports noted that DNA polymorphisms vary clinical manifestations of severe infection. Taken together, in premature infants, severe infection and high serum IL-18 may cause damages to immature cells probably through TLR-mediated signals, and DNA polymorphisms may play an important role to modify the sensitivity to the signals.