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首页> 外文期刊>Cellular Signalling >Combined CpG and poly I: C stimulation of monocytes results in unique signaling activation not observed with the individual ligands
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Combined CpG and poly I: C stimulation of monocytes results in unique signaling activation not observed with the individual ligands

机译：CpG和poly I：C联合刺激单核细胞导致独特的信号激活，单个配体未观察到

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Toll-like receptors (TLRs) bind to components of microbes, activate cellular signal transduction pathways and stimulate innate immune responses. Previously, we have shown in chicken monocytes that the combination of CpG, the ligand for TLR21 (the chicken equivalent of TLR9), and poly I:C, the ligand for TLR3, results in a synergistic immune response. In order to further characterize this synergy, kinome analysis was performed on chicken monocytes stimulated with either unmethylated CpG oligodeoxynucleotides (CpG) and polyinosinic-polycytidylic acid (poly I:C) individually or in combination for either 1. h or 4. h. The analysis was carried out using chicken species-specific peptide arrays to study the kinase activity induced by the two ligands. The arrays are comprised of kinase target sequences immobilized on an array surface. Active kinases phosphorylate their respective target sequences, and these phosphorylated peptides are then visualized and quantified. A significant number of peptides exhibited altered phosphorylation when CpG and poly I:C were given together, that was not observed when either CpG or poly I:C was given separately. The unique, synergistic TLR agonist affected peptides represent protein members of signaling pathways including calcium signaling pathway, cytokine-cytokine receptor interaction and Endocytosis at the 1. h time point. At the 4. h time point, TLR agonist synergy influenced pathways included Adipocytokine signaling pathway, cell cycle, calcium signaling pathway, NOD-like receptor signaling pathway and RIG-I-like receptor signaling pathway. Using nitric oxide (NO) production as the readout, TLR ligand synergy was also investigated using signaling protein inhibitors. A number of inhibitors were able to inhibit NO response in cells given CpG alone but not in cells given both CpG and poly I:C, as poly I:C alone does not elicit a significant NO response. The unique peptide phosphorylation induced by the combination of CpG and poly I:C and the unique signaling protein requirements for synergy determined by inhibitor assays both show that synergistic signaling is not a simple addition of TLR pathways. A set of secondary pathways activated by the ligand combination are proposed, leading to the activation of cAMP response element-binding protein (CREB), nuclear factor κB (NFκB) and ultimately of inducible nitric oxide synthase (iNOS). Since many microbes can stimulate more than one TLR, this synergistic influence on cellular signaling may be an important consideration for the study of immune response and what we consider to be the canonical TLR signaling pathways.
机译：Toll样受体（TLR）与微生物成分结合，激活细胞信号转导途径并刺激先天免疫应答。以前，我们已经在鸡单核细胞中显示CpG（TLR21的配体）（TLR9的鸡等效物）和poly I：C（TLR3的配体）的组合可产生协同免疫反应。为了进一步表征这种协同作用，分别对未甲基化的CpG寡脱氧核苷酸（CpG）和多肌苷酸-聚胞苷酸（poly I：C）刺激的鸡单核细胞进行了kinome分析，时间为1. h或4. h。使用鸡种特异性肽阵列进行分析以研究由两个配体诱导的激酶活性。阵列由固定在阵列表面上的激酶靶序列组成。活性激酶将其各自的靶序列磷酸化，然后将这些磷酸化的肽可视化并进行定量。一起使用CpG和poly I：C时，大量肽的磷酸化改变，而当单独使用CpG或poly I：C时则未观察到。独特的，协同TLR激动剂影响的肽代表信号途径的蛋白质成员，包括1.h时间点的钙信号传导途径，细胞因子-细胞因子受体相互作用和胞吞作用。在4.h时间点，TLR激动剂协同作用影响的途径包括脂肪细胞因子信号传导途径，细胞周期，钙信号传导途径，NOD样受体信号通路和RIG-1样受体信号通路。使用一氧化氮（NO）的产生作为读数，还使用信号蛋白抑制剂研究了TLR配体协同作用。许多抑制剂能够在单独使用CpG的细胞中抑制NO反应，但不能在同时使用CpG和poly I：C的细胞中抑制NO反应，因为单独的poly I：C不会引起明显的NO反应。 CpG和聚I：C的组合诱导的独特肽磷酸化和抑制剂测定确定的协同作用的独特信号蛋白要求均显示协同信号不是TLR途径的简单添加。提出了一组由配体结合激活的次级途径，从而导致cAMP反应元件结合蛋白（CREB），核因子κB（NFκB）和最终诱导型一氧化氮合酶（iNOS）的激活。由于许多微生物可以刺激一个以上的TLR，因此这种对细胞信号传导的协同影响可能是研究免疫应答和我们认为是典型的TLR信号通路的重要考虑因素。

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