Neonatal Plasma Polarizes TLR4-Mediated Cytokine Responses towards Low IL-12p70 and High IL-10 Production via Distinct Factors

Human neonates are highly susceptible to infection, which may be due in part to impaired innate immune function. Neonatal Toll-like receptor (TLR) responses are biased against the generation of pro-inflammatory/Th1-polarizing cytokines, yet the underlying mechanisms are incompletely defined. Here, we demonstrate that neonatal plasma polarizes TLR4-mediated cytokine production. When exposed to cord blood plasma, mononuclear cells (MCs) produced significantly lower TLR4-mediated IL-12p70 and higher IL-10 compared to MC exposed to adult plasma. Suppression by neonatal plasma of TLR4-mediated IL-12p70 production, but not induction of TLR4-mediated IL-10 production, was maintained up to the age of 1 month. Cord blood plasma conferred a similar pattern of MC cytokine responses to TLR3 and TLR8 agonists, demonstrating activity towards both MyD88-dependent and MyD88-independent agonists. The factor causing increased TLR4-mediated IL-10 production by cord blood plasma was heat-labile, lost after protein depletion and independent of lipoprotein binding protein (LBP) or soluble CD14 (sCD14). The factor causing inhibition of TLR4-mediated IL-12p70 production by cord blood plasma was resistant to heat inactivation or protein depletion and was independent of IL-10, vitamin D and prostaglandin E2. In conclusion, human neonatal plasma contains at least two distinct factors that suppress TLR4-mediated IL-12p70 production or induce IL-10 or production. Further identification of these factors will provide insight into the ontogeny of innate immune development and might identify novel targets for the prevention and treatment of neonatal infection.

人类新生儿极易罹患感染，这在一定程度上与其固有免疫功能受损有关。新生儿Toll样受体（Toll-like receptor, TLR）的应答偏向于无法生成促炎/Th1极化细胞因子，但其潜在机制尚未完全阐明。
本研究证实，新生儿血浆可调控TLR4介导的细胞因子产生。与暴露于成人血浆的单核细胞（mononuclear cells, MCs）相比，暴露于脐带血浆的单核细胞所产生的TLR4介导的IL-12p70水平显著降低，而IL-10水平则显著升高。新生儿血浆对TLR4介导的IL-12p70产生的抑制效应（而非对TLR4介导的IL-10产生的诱导效应）可维持至出生后1月龄。脐带血浆可使单核细胞对TLR3及TLR8激动剂产生类似的细胞因子应答模式，表明其对MyD88依赖型与MyD88非依赖型激动剂均具有调控活性。
导致脐带血浆促进TLR4介导的IL-10产生的因子为热不稳定物质，经蛋白去除后活性丧失，且与脂蛋白结合蛋白（lipoprotein binding protein, LBP）或可溶性CD14（soluble CD14, sCD14）无关。而介导脐带血浆抑制TLR4介导的IL-12p70产生的因子则可耐受热灭活与蛋白去除，且不受IL-10、维生素D及前列腺素E2的影响。
综上，人类新生儿血浆中至少存在两种截然不同的因子，分别可抑制TLR4介导的IL-12p70产生或诱导IL-10生成。进一步鉴定这些因子将有助于深入解析固有免疫发育的个体发生过程，并可为新生儿感染的防治提供全新靶点。