The hemagglutinin-neuramidinase protein of Newcastle disease virus upregulates expression of the TRAIL gene in murine natural killer cells through the activation of Syk and NF-κB.
The hemagglutinin-neuramidinase protein of Newcastle disease virus upregulates expression of the TRAIL gene in murine natural killer cells through the activation of Syk and NF-κB.
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新城疫病毒的血凝素神经氨酸酶蛋白通过激活 Syk 和 NF-κ B 上调小鼠自然杀伤细胞中 TRAIL 基因的表达
DOI：
10.1371/journal.pone.0178746
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Fan XH
中科院分区：
文献类型：
--
作者：
Liang Y;Song DZ;Liang S;Zhang ZF;Gao LX;Fan XH
纽卡斯尔病病毒（NDV）在体内外均具有杀肿瘤活性。然而，导致这种活动的机制尚不清楚。自然杀伤细胞能够通过多种途径诱导肿瘤细胞凋亡，包括肿瘤坏死因子相关的凋亡诱导配体-死亡受体途径。我们先前表明，NK和T细胞暴露于NDV导致增强的杀肿瘤活性，其通过干扰素γ依赖性途径由TRAIL基因的上调表达介导。涉及TRAIL表达上调的其他途径尚待鉴定。在目前的研究中，我们使用了IFN-γ受体1基因功能失活的小鼠。我们在NDV刺激的NK细胞中鉴定了IFN-γ非依赖性TRAIL途径。血凝素-神经氨酸酶通过与NKp 46受体结合来诱导IFN-R1-/- NK细胞中TRAIL基因的表达。用抗HN的中和性单克隆抗体预处理NDV或NK细胞去唾液酸化可抑制这种上调。HN诱导的IFN-R1-/- NK细胞中脾酪氨酸激酶和IκBα磷酸化增加。用HN中和单克隆抗体、药理学双唾液酸化或Syk抑制剂处理可降低Syk和IκBα磷酸化水平。我们的结论是，杀伤活化受体途径参与了NDV刺激的NK细胞的IFN-γ非依赖性TRAIL表达，并且这些TRAIL被Syk和NF-κB激活。
Newcastle disease virus (NDV) is responsible for tumoricidal activity in vitro and in vivo. However, the mechanisms that lead to this activity are unclear. Natural killer cells are able to induce apoptosis of tumor cells through multiple pathways, including the tumor necrosis factor-related apoptosis-inducing ligand-death receptor pathway. We previously showed that exposure of NK and T cells to NDV resulted in enhanced tumoricidal activity that was mediated by upregulated expression of the TRAIL gene, via an interferon gamma -dependent pathway. Other pathways involved in the upregulated expression of TRAIL are yet to be identified. In the current study, we used mice in which the IFN-γ receptor one gene was inactivated functionally. We identified an IFN-γ-independent TRAIL pathway in the NDV-stimulated NK cells. Hemagglutinin-neuramidinase induced expression of the TRAIL gene in IFN-R1-/- NK cells by binding to the NKp46 receptor. This upregulation was inhibited by pretreatment of NDV with a neutralizing monoclonal antibody against HN, or desialylation of NK cells. Phosphorylation of spleen tryosine kinases and IκBα was increased in HN-induced IFN-R1-/- NK cells. Treatment with the HN neutralizing monoclonal antibody, pharmacological disialylation, or a Syk inhibitor decreased Syk and IκBα phosphorylation levels. We concluded that killer activation receptors pathway is involved in the IFN-γ-independent TRAIL expression of NDV-stimulated NK cells, and these are activated by Syk and NF-κB.