Toxoplasma gondii triggers myeloid differentiation factor 88-dependent IL-12 and chemokine ligand 2 (monocyte chemoattractant protein 1) responses using distinct parasite molecules and host receptors
Toxoplasma gondii triggers myeloid differentiation factor 88-dependent IL-12 and chemokine ligand 2 (monocyte chemoattractant protein 1) responses using distinct parasite molecules and host receptors
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DOI：
10.4049/jimmunol.172.11.6954
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发表时间：
2004-06-01
影响因子：
4.4
通讯作者：
Denkers, EY
中科院分区：
文献类型：
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作者：
Del Rio, L;Butcher, BA;Denkers, EY
Toll样受体（TLR）通过共同的衔接分子髓样分化因子88（MyD 88）的信号是必不可少的促炎性细胞因子对许多微生物病原体的反应。在这项研究中，我们报告，弓形虫触发中性粒细胞IL-12和趋化因子配体2（CCL 2;单核细胞趋化蛋白1）的生产严格依赖于功能MyD 88。然而，反应是不同的。虽然我们确定TLR 2作为受体触发CCL 2的生产，寄生虫诱导的IL-12的释放并不涉及这种TLR。在用IFN-γ活化中性粒细胞后，IL-12和CCL 2的产生增加。然而，IFN-γ对IL-12而不是CCL 2的协同作用依赖于Stat 1信号转导。虽然IL-10是弓形虫触发的中性粒细胞IL-12释放的有效下调因子，但该细胞因子对寄生虫诱导的CCL 2产生没有影响。可溶性速殖子Ag分馏表明，CCL 2-和IL-12诱导活性是生化不同的。重要的是，弓形虫亲环素-18，一种先前显示诱导树突状细胞IL-12的分子，不参与中性粒细胞IL-12的产生。我们的研究结果首次表明T.弓形虫具有多种触发不同MyD 88依赖性信号级联的分子，这些途径是独立调节的，并且它们导致细胞因子产生的不同特征。
Toll-like receptors (TLR) that signal through the common adaptor molecule myeloid differentiation factor 88 (MyD88) are essential in proinflammatory cytokine responses to many microbial pathogens. In this study we report that Toxoplasma gondii triggers neutrophil IL-12 and chemokine ligand 2 (CCL2; monocyte chemoattractant protein 1) production in strict dependence upon functional MyD88. Nevertheless, the responses are distinct. Although we identify TLR2 as the receptor triggering CCL2 production, parasite-induced IL-12 release did not involve this TLR. The production of both IL-12 and CCL2 was increased after neutrophil activation with IFN-gamma. However, the synergistic effect of IFN-gamma on IL-12, but not CCL2, was dependent upon Stat1 signal transduction. Although IL-10 was a potent down-regulator of Toxoplasma-triggered neutrophil IL-12 release, the cytokine had no effect on parasite-induced CCL2 production. Soluble tachyzoite Ag fractionation demonstrated that CCL2- and IL-12 inducing activities are biochemically distinct. Importantly, Toxoplasma cyclophilin-18, a molecule previously shown to induce dendritic cell IL-12, was not involved in neutrophil IL-12 production. Our results show for the first time that T. gondii possesses multiple molecules triggering distinct MyD88-dependent signaling cascades, that these pathways are independently regulated, and that they lead to distinct profiles of cytokine production.