Immunomodulation via novel use of TLR4 by the filarial nematode phosphorylcholine-containing secreted product, ES-62
Immunomodulation via novel use of TLR4 by the filarial nematode phosphorylcholine-containing secreted product, ES-62
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DOI：
10.4049/jimmunol.174.1.284
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发表时间：
2005-01-01
影响因子：
4.4
通讯作者：
Harnett, MM
中科院分区：
文献类型：
--
作者：
Goodridge, HS;Marshall, FA;Harnett, MM
丝虫是脊椎动物（包括人类）的寄生虫，分泌免疫调节分子进入宿主环境。我们以前已经证明，这样一个分子，磷酸胆碱含糖蛋白ES-62，作用偏向于抗炎/Th 2表型，这是有益于蠕虫的生存和宿主的健康的免疫反应。例如，虽然ES-62最初诱导巨噬细胞产生低水平的IL-12和TNF-α，但暴露于寄生虫产物最终使细胞不能响应于经典刺激物如LPS/IFN-γ产生这些细胞因子。我们已经研究了TLR参与靶细胞识别ES-62的可能性，因为磷酸胆碱，一种常见的病原体相关分子模式，似乎是负责ES-62的许多免疫调节特性。我们现在证明，ES-62介导的，低水平的IL-12和TNF-α的巨噬细胞和树突状细胞的生产被废除在MyD 88和TLR 4，但不是TLR 2，敲除小鼠暗示TLR 4在识别ES-62的这些细胞和MyD 88在产生的细胞内信号的转导。我们还表明，ES-62抑制IL-12诱导TLR配体以外的LPS，细菌脂肽（TLR 2）和CpG（TLR 9），通过这种TLR 4依赖性途径。令人惊讶的是，来自LPS无反应的TLR 4突变型C3 H/HeJ小鼠的巨噬细胞和树突状细胞对ES-62反应正常。这是第一份报告，以证明调制的细胞因子反应的病原体产品可以废除来自TLR 4基因敲除的细胞，但不是C3 H/HeJ小鼠，这表明存在一种新的机制TLR 4介导的免疫调节。
Filarial nematodes, parasites of vertebrates, including humans, secrete immunomodulatory molecules into the host environment. We have previously demonstrated that one such molecule, the phosphorylcholine-containing glycoprotein ES-62, acts to bias the immune response toward an anti-inflammatory/Th2 phenotype that is conducive to both worm survival and host health. For example, although ES-62 initially induces macrophages to produce low levels of IL-12 and TNF-alpha, exposure to the parasite product ultimately renders the cells unable to produce these cytokines in response to classic stimulators such as LPS/IFN-gamma. We have investigated the possibility that a TLR is involved in the recognition of ES-62 by target cells, because phosphorylcholine, a common pathogen-associated molecular pattern, appears to be responsible for many of the immunomodulatory properties of ES-62. We now demonstrate that ES-62-mediated, low level IL-12 and TNF-alpha production by macrophages and dendritic cells is abrogated in MyD88 and TLR4, but not TLR2, knockout, mice implicating TLR4 in the recognition of ES-62 by these cells and MyD88 in the transduction of the resulting intracellular signals. We also show that ES-62 inhibits IL-12 induction by TLR ligands other than LPS, bacterial lipopeptide (TLR2) and CpG (TLR9), via this TLR4-dependent pathway. Surprisingly, macrophages and dendritic cells from LPS-unresponsive, TLR4-mutant C3H/HeJ mice respond normally to ES-62. This is the first report to demonstrate that modulation of cytokine responses by a pathogen product can be abrogated in cells derived from TLR4 knockout, but not C3H/HeJ mice, suggesting the existence of a novel mechanism of TLR4-mediated immunomodulation.