Adenosine Shapes Neonatal Toll-like Receptor Function

描述（由申请人提供）：新生儿感染的风险增加，但其易感性的机制尚未完全确定。Toll样受体（TLR）在识别微生物组分（包括由广泛的细菌表达的细菌脂肽（BLP））中起关键作用，其通过TLR 1/2（三酰化BLP）或TLR 2/6（二酰化BLP）的异源二聚体激活单核细胞。初步研究表明，尽管TLR和相关的信号传导组分表达正常，但人新生儿血单核细胞在BLP诱导的促炎和Th 1极化细胞因子肿瘤坏死因子-α（TNF-α）的合成中表现出2至3个对数的损伤，同时保留了BLP诱导的IL-6（一种具有抗炎和Th 2极化活性的细胞因子）的产生。新生儿TNF-α产生的类似损伤在对E. coli K1/r，一种表达BLP的致病菌。我们已经发现，受损的BLP-和E。Col 1诱导的新生儿血液单核细胞产生TNF-α可归因于血浆腺苷的作用，血浆腺苷是一种具有免疫调节特性的内源性嘌呤代谢物，在应激或缺氧条件下从细胞中释放。新生儿单核细胞对腺苷诱导的TNF-α产生的抑制和腺苷诱导的环AMP产生特别敏感，环AMP是一种抑制TNF-α合成同时保持IL-6产生的细胞内代谢物。该项目的总体目标是描述新生儿腺苷系统在调节新生儿血液单核细胞TLR介导的先天免疫应答中的作用。这一目标将通过三个具体目标来实现：（1）确定新生儿单核细胞对腺苷更敏感的机制，（2）确定介导BLP-和E.大肠杆菌诱导新生儿血单核细胞产生TNF-α;（3）研究腺苷受体参与导致BLP-和E.大肠杆菌诱导单核细胞产生TNF-α，同时保留IL-6的产生。机制分析将确定腺苷如何改变新生儿TLR介导的免疫反应。总的来说，这些研究将加深我们对人类新生儿独特生理学如何从根本上改变出生时先天免疫的理解。

DESCRIPTION (provided by applicant): Newborns are at increased risk of infection yet the mechanisms underlying their susceptibility are incompletely defined. Toll-like receptors (TLRs) play crucial roles in the recognition of microbial components including bacterial lipopeptides (BLPs), expressed by a wide-range of bacteria, that activate monocytes via a heterodimer of TLR1/2 (triacylated BLPs) or TLR2/6 (diacylated BLPs). Preliminary studies indicate that despite normal expression of TLRs and associated signaling components, human newborn blood monocytes demonstrate a 2- to 3-log impairment in BLP-induced synthesis of pro-inflammatory and Th1-polarizing cytokine tumor necrosis factor-alpha (TNF-alpha) with preservation of BLP-induced production of IL-6, a cytokine with anti-inflammatory and Th2-polarizing activities. Similar impairment in neonatal TNF-alpha production is evident in response to E. coli K1/r, a pathogenic bacterium that expresses BLPs. We have discovered that impaired BLP- and E. col1- induced TNF-alpha production from neonatal blood monocytes is attributable to the action of plasma adenosine, an endogenous purine metabolite with immunomodulatory properties that is released from cells under conditions of stress or hypoxia. Neonatal mononuclear cells are especially sensitive to adenosine-induced inhibition of TNF-alpha production and to adenosine-induced production of cyclic AMP, an intracellular metabolite that inhibits TNF-alpha synthesis while preserving IL-6 production. The overall goal of this project is to characterize the role of the neonatal adenosine system in modulating TLR-mediated innate immune responses in neonatal blood monocytes. This goal will be accomplished through three specific aims: (1) to determine the mechanism for the greater adenosine sensitivity of neonatal mononuclear cells, (2) to define the adenosine receptor sub-type(s) that mediate inhibition of BLP- and E. coli-induced TNF-alpha production from neonatal blood monocytes; and (3) to characterize the mechanism by which engagement of adenosine receptors results in diminished BLP- and E. coli-induced monocyte TNF-alpha production while preserving IL-6 production. Mechanistic analysis will define how adenosine alters neonatal TLR-mediated immune responses. As a whole, these studies will deepen our understanding of how the unique physiology of the human newborn fundamentally alters innate immunity at birth.