Substance P inhibits natural killer cell cytotoxicity through the neurokinin-1 receptor
Substance P inhibits natural killer cell cytotoxicity through the neurokinin-1 receptor
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DOI：
10.1189/jlb.0410200
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发表时间：
2011-01-01
影响因子：
5.5
通讯作者：
Orange, Jordan S.
中科院分区：
文献类型：
--
作者：
Monaco-Shawver, Linda;Schwartz, Lynnae;Orange, Jordan S.
SP是一种强大的神经免疫调节剂，通过连接神经激肽受体家族的成员发挥作用，其中NK1R在免疫细胞中广泛表达。与人类一样，在与NK细胞功能受损相关的病理状态下，如抑郁症和HIV感染，循环中的SP水平会升高，我们假设SP对NK细胞具有直接的抑制作用。我们对克隆性人NK细胞系(YTS)和体外培养的人NK细胞进行了研究，发现在体外NK细胞和YTS NK细胞系中表达截短型和全长NK1R亚型，并与其结合。YTS细胞与10(-6)M SP和体外NK细胞与10(-5)M SP孵育后，对细胞毒作用的抑制率接近20%，脱颗粒减少。这种对细胞毒性的抑制作用可被NK1R拮抗剂CP96,345部分阻止。SP对YTS或体外NK细胞的作用既不下调NCR的表达，也不影响受体诱导的NF-kappaB的激活。然而，用SP预先孵育YTS细胞确实缩短了靶细胞参与引起的典型的长时间细胞内钙升高，并减少了触发受体诱导的PERK。因此，SP有可能调节NK细胞的功能，并作用于神经激肽受体下游，调节NK细胞激活信号。这一机制可能与某些疾病状态下的NK细胞功能受损有关，与循环中SP的升高有关。这一系统的拮抗可能为在特定的人类疾病中增强NK细胞的治疗功能提供了机会。J.Leukoc。比奥尔。89：113-125；2011。
SP is a potent neuroimmunomodulator that functions through ligating members of the neurokinin receptor family, one of which, NK1R, is widely expressed in immune cells. As in humans, circulating SP levels are increased in pathologic states associated with impairment of NK cell functions, such as depression and HIV infection, we hypothesized that SP has a direct, inhibitory effect upon NK cells. We have studied a clonal human NK cell line (YTS) as well as ex vivo human NK cells and have determined that truncated and full-length NK1R isoforms are expressed in and SP bound by ex vivo NK cells and the YTS NK cell line. Incubation of YTS cells with 10(-6) M SP and ex vivo NK cells with 10(-5) M SP inhibited cytotoxic ability by similar to 20% and reduced degranulation. This inhibitory effect upon cytotoxicity was partially prevented by the NK1R antagonist CP96,345. The treatment of YTS or ex vivo NK cells with SP neither down-modulated NCR expression nor affected triggering receptor-induced NF-kappa B activation. Preincubation of YTS cells with SP, however, did abbreviate the typically prolonged intracellular calcium increase induced by target cell engagement and reduced triggering receptor-induced pERK. Thus, SP has the potential to regulate NK cell functions and acts downstream from neurokinin receptors to modulate NK cell activation signaling. This mechanism may contribute to impairment of NK cell function in certain disease states associated with increased circulating SP. Antagonism of this system may present an opportunity to augment NK cell function therapeutically in selected human diseases. J. Leukoc. Biol. 89: 113-125; 2011.