An Impaired Inflammatory Cytokine Response to Gram-Negative LPS in Human Neonates is Associated with the Defective TLR-Mediated Signaling Pathway
An Impaired Inflammatory Cytokine Response to Gram-Negative LPS in Human Neonates is Associated with the Defective TLR-Mediated Signaling Pathway
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DOI：
10.1007/s10875-015-0128-6
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发表时间：
2015-02-01
影响因子：
9.1
通讯作者：
Wang, Jian
中科院分区：
文献类型：
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作者：
Li, Yi Ping;Yu, Sheng Lin;Wang, Jian
采集30例健康足月择期剖宫产新生儿脐血和25例健康成人志愿者外周血。流式细胞仪检测单个核细胞表面CD14、TLR4、TLR2、磷酸化核因子-kappaB p65和p38的表达。新生儿全血经TLR4激动剂LPS刺激后，体外产生的肿瘤坏死因子-α和IL-1β显著低于成人全血，而TLR2激动剂PGN对其无明显影响。与炎性细胞因子对内毒素刺激的反应减弱相一致，新生儿单核细胞表现为TLR介导的信号转导通路显著受损，其特征是CD14和TLR4的表达下调，并抑制了内毒素刺激后核因子-kappa B p65在Ser536和p38的磷酸化。此外，新生儿的TLR4(+)/CD14(+)单核细胞百分率明显低于成人。这些结果表明，与成人相比，人类新生儿在先天免疫相关的炎症细胞因子反应方面表现出缺陷，这是由于其TLR信号通路的缺陷，这可能使他们更容易受到微生物的感染。
Cord blood from 30 healthy newborns of full-term elective cesarean sections and peripheral blood from 25 healthy adult volunteers were collected. Ex vivo production of inflammatory cytokines was assessed by cytometric bead array, and expression of CD14, TLR4, TLR2, phosphorylated NF-kappa B p65 and p38 on monocytes were detected by FACScan analysis.Neonatal whole blood showed significantly decreased ex vivo TNF-alpha and IL-1 beta production in response to stimulation with the TLR4 agonist LPS, but not the TLR2 agonist PGN, when compared with adult whole blood. Consistent with the diminished inflammatory cytokine response to LPS stimulation, neonatal monocytes exhibited substantially impaired TLR-mediated signal transduction pathways characterized by down-regulated expression of CD14 and TLR4, and suppressed phosphorylation of NF-kappa B p65 at Ser536 and p38 following LPS stimulation. In addition, neonates had a significantly lower percentage of TLR4(+)/CD14(+) monocytes than adults.These results indicate that in contrast to the adult, human neonates display deficiencies in innate immunity-associated inflammatory cytokine responses due to their defective TLR signaling pathways, which may render them more susceptible to microbial infection.