The adenosine system selectively inhibits TLR-mediated TNF-α production in the human newborn
The adenosine system selectively inhibits TLR-mediated TNF-α production in the human newborn
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DOI：
10.4049/jimmunol.177.3.1956
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发表时间：
2006-08-01
影响因子：
4.4
通讯作者：
Wessels, Michael R.
中科院分区：
文献类型：
--
作者：
Levy, Ofer;Coughlin, Melissa;Wessels, Michael R.
人类新生儿易受微生物感染，疫苗应答较差，但其易感性的机制尚未完全确定。我们以前报道过，尽管TLR和相关信号中间体的基础表达正常，但人新生儿脐带血单核细胞对三酰化（TLR 2/1）和二酰化（TLR 2/6）细菌脂肽（BLP）的TNF-α产生严重受损。我们现在证明，在明显的对比，BLP诱导的IL-6，一种细胞因子与抗炎和Th 2极化特性的合成，实际上是更大的新生儿比成人。值得注意的是，新生儿血浆赋予显著降低的BLP诱导的单核细胞TNF-α合成，同时保留IL-6合成，反映了新生儿血浆中存在可溶性低分子量抑制因子（< 10 kDa），我们将其鉴定为腺苷，一种具有免疫调节特性的内源性嘌呤代谢物。新生儿腺苷系统还抑制响应于已知表达TLR 2激动剂活性的完整微生物颗粒的TNF-α产生，所述完整微生物颗粒包括单核细胞增生李斯特菌、大肠杆菌（表达BLP）和酵母聚糖颗粒。新生儿TNF-α产生的选择性抑制是由于独特的新生儿腺苷系统，包括新生儿血浆中相对高的腺苷浓度和新生儿单核细胞对腺苷A3受体介导的cAMP积累的敏感性提高，cAMP是抑制TLR介导的TNF-α合成但保留IL-6产生的第二信使。我们的结论是，不同的腺苷系统的新生儿极化TLR介导的细胞因子的生产在围产期期间，从而可能调节其先天性和适应性免疫反应。
Human newborns are susceptible to microbial infection and mount poor vaccine responses, yet the mechanisms underlying their susceptibility are incompletely defined. We have previously reported that despite normal basal expression of TLRs and associated signaling intermediates, human neonatal cord blood monocytes demonstrate severe impairment in TNF-alpha production in response to triacylated (TLR 2/1) and diacylated (TLR 2/6) bacterial lipopeptides (BLPs). We now demonstrate that in marked contrast, BLP-induced synthesis of IL-6, a cytokine with anti-inflammatory and Th2-polarizing properties, is actually greater in neonates than adults. Remarkably, newborn blood plasma confers substantially reduced BLP-induced monocyte synthesis of TNF-a, while preserving IL-6 synthesis, reflecting the presence in neonatal blood plasma of a soluble, low molecular mass inhibitory factor (< 10 kDa) that we identify as adenosine, an endogenous purine metabolite with immunomodulatory properties. The neonatal adenosine system also inhibits TNF-alpha production in response to whole microbial particles known to express TLR2 agonist activity, including Listeria monocytogenes, Escherichia coli (that express BLPs), and zymosan particles. Selective inhibition of neonatal TNF-alpha production is due to the distinct neonatal adenosine system, including relatively high adenosine concentrations in neonatal blood plasma and heightened sensitivity of neonatal mononuclear cells to adenosine A3 receptor-mediated accumulation of cAMP, a second messenger that inhibits TLR-mediated TNF-alpha synthesis but preserves IL-6 production. We conclude that the distinct adenosine system of newborns polarizes TLR-mediated cytokine production during the perinatal period and may thereby modulate their innate and adaptive immune responses.