N6-isopentenyladenosine, an endogenous isoprenoid end product, directly affects cytotoxic and regulatory functions of human NK cells through FDPS modulation
N6-isopentenyladenosine, an endogenous isoprenoid end product, directly affects cytotoxic and regulatory functions of human NK cells through FDPS modulation
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DOI：
10.1189/jlb.0413190
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发表时间：
2013-12-01
影响因子：
5.5
通讯作者：
Bifulco, Maurizio
中科院分区：
文献类型：
--
作者：
Ciaglia, Elena;Pisanti, Simona;Bifulco, Maurizio
类异戊二烯衍生物iPA与IL-2协同用于人原代NK细胞的扩增和细胞毒性的分子机制。iPA是一种天然存在的核苷，其异戊烯基部分来源于甲羟戊酸途径，具有公认的抗肿瘤活性。与人类V9 V2 T细胞显示的对磷酸化抗原（如IPP）的独特特异性类似，我们在此首次报告了iPA选择性扩增并直接靶向人类NK细胞的能力。有趣的是，亚微摩尔剂量的iPA刺激静息的人NK细胞，并与IL-2协同作用，以诱导离体稳健活化，与IL-2单一细胞因子处理相比，CCL 5和CCL 3显著分泌，TNF-和IFN-产生大幅增加。此外，iPA促进NK细胞增殖并上调特异性NK细胞活化受体的表达以及CD 69和CD 107 a表达。因此，这种表型与针对肿瘤靶标的显著更大的细胞毒性相关。在分子水平上，iPA导致IL-2 R下游MAPK信号传导中间体的选择性、有效活化。该效果至少部分地由FDPS活性的精细调节产生，FDPS活性与刺激人T细胞所涉及的酶相同。iPA驱动的FDPS调节可引起翻译后异戊烯化的增强，这对于NK信号传导和效应子功能中的关键蛋白（如Ras）的生物活性至关重要。iPA的这些非预期性质为甲羟戊酸途径中间体的免疫调节作用提供了额外证据，并为该分子作为免疫调节药物开辟了新的治疗前景。
Molecular mechanisms by which the isoprenoid derivative iPA synergizes with IL-2, for the expansion and cytotoxicity of human primary NK cells. iPA is a naturally occurring nucleoside with an isopentenyl moiety derived from the mevalonate pathway and a well-established anti-tumor activity. In analogy to the unique specificity for phosphoantigens, such as IPP, shown by human V9V2 T cells, here, we report for the first time the ability of iPA to selectively expand and directly target human NK cells. Interestingly, submicromolar doses of iPA stimulate resting human NK cells and synergize with IL-2 to induce a robust activation ex vivo with significant secretion of CCL5 and CCL3 and a large increase in TNF- and IFN- production when compared with IL-2 single cytokine treatment. Moreover, iPA promotes NK cell proliferation and up-regulates the expression of specific NK cell-activating receptors, as well as CD69 and CD107a expression. Accordingly, this phenotype correlates with significantly greater cytotoxicity against tumor targets. At the molecular level, iPA leads to a selective, potent activation of MAPK signaling intermediaries downstream of the IL-2R. The effect results, at least in part, from the fine modulation of the FDPS activity, the same enzyme implicated in the stimulation of the human T cells. The iPA-driven modulation of FDPS can cause an enhancement of post-translational prenylation essential for the biological activity of key proteins in NK signaling and effector functions, such as Ras. These unanticipated properties of iPA provide an additional piece of evidence of the immunoregulatory role of the intermediates of the mevalonate pathway and open novel therapeutic perspectives for this molecule as an immune-modulatory drug.