Histamine reduces susceptibility to natural killer cells via down-regulation of NKG2D ligands on human monocytic leukaemia THP-1 cells
Histamine reduces susceptibility to natural killer cells via down-regulation of NKG2D ligands on human monocytic leukaemia THP-1 cells
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DOI：
10.1111/j.1365-2567.2012.03565.x
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发表时间：
2012-05-01
期刊：
影响因子：
6.4
通讯作者：
Sugawara, Shunji
中科院分区：
文献类型：
--
作者：
Nagai, Yasuhiro;Tanaka, Yukinori;Sugawara, Shunji
自然杀伤细胞（NK）2D组（NKG2D）是NK细胞上表达的一种关键活化受体，其与靶细胞上的配体相互作用在肿瘤发生中起重要作用。然而，组胺对肿瘤细胞上NKG2D配体的影响尚不清楚。在这里，我们表明，人单核细胞白血病THP-1细胞组成型表达MHC I类相关链A（MICA）和UL16结合蛋白1在其表面上，和组胺孵育减少表达的剂量依赖性和时间依赖性的方式，通过流式细胞术评估。干扰素-？增加NKG2D配体的表面表达，并且这种增加被组胺显著减弱。组胺H1受体（H1R）激动剂2-吡啶基乙胺和H2R激动剂二甲双胍下调NKG2D配体的表达，A23187和毛喉素分别激活H1R和H2R信号传导具有相同的作用，表明组胺诱导的NKG2D配体下调由H1R和H2R介导。定量逆转录-PCR显示，组胺未显著改变NKG2D配体和相关microRNA的mRNA水平。组胺下调内质网蛋白5的表面表达，抑制基质金属蛋白酶并不损害这种下调，表明蛋白水解脱落不参与。相反，药理学抑制蛋白质转运和蛋白酶体废除它，和组胺增强泛素化的MICA。此外，组胺治疗显着降低对NK细胞介导的细胞毒性的敏感性。这些结果表明，组胺通过激活H1R和H2R介导的泛素蛋白酶体途径下调NKG2D配体，从而降低对NK细胞的易感性。
Natural killer (NK) group 2D (NKG2D) is a key activating receptor expressed on NK cells, whose interaction with ligands on target cells plays an important role in tumorigenesis. However, the effect of histamine on NKG2D ligands on tumour cells is unclear. Here we showed that human monocytic leukaemia THP-1 cells constitutively express MHC class I-related chain A (MICA) and UL16-binding protein 1 on their surface, and incubation with histamine reduced the expression in a dose-dependent and time-dependent manner as assessed by flow cytometry. Interferon-? augmented the surface expression of the NKG2D ligands, and this augmentation was significantly attenuated by histamine. The histamine H1 receptor (H1R) agonist 2-pyridylethylamine and H2R agonist dimaprit down-regulated the expression of NKG2D ligands, and activation of H1R and H2R signalling by A23187 and forskolin, respectively, had the same effect, indicating that the histamine-induced down-regulation of NKG2D ligands is mediated by H1R and H2R. Quantitative reverse transcription-PCR showed that mRNA levels of the NKG2D ligands and relevant microRNAs were not significantly changed by histamine. Histamine down-regulated the surface expression of endoplasmic reticulum protein 5, and inhibition of matrix metalloproteinases did not impair this down-regulation, indicating that proteolytic shedding was not involved. Instead, pharmacological inhibition of protein transport and proteasome abrogated it, and histamine enhanced ubiquitination of MICA. Furthermore, histamine treatment significantly reduced susceptibility to NK cell-mediated cytotoxicity. These results suggest that histamine down-regulates NKG2D ligands through the activation of an H1R- and H2R-mediated ubiquitinproteasome pathway and consequently reduces susceptibility to NK cells.