Interferon-activated neutrophils store a TNF-related apoptosis-inducing ligand (TRAIL/Apo-2 ligand) intracellular pool that is readily mobilizable following exposure to proinflammatory mediators
Interferon-activated neutrophils store a TNF-related apoptosis-inducing ligand (TRAIL/Apo-2 ligand) intracellular pool that is readily mobilizable following exposure to proinflammatory mediators
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DOI：
10.1189/jlb.0805431
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发表时间：
2006-01-01
影响因子：
5.5
通讯作者：
Tecchio, C
中科院分区：
文献类型：
--
作者：
Cassatella, MA;Huber, V;Tecchio, C
中性粒细胞是多功能细胞，不仅在炎症过程中发挥作用，而且在免疫和抗肿瘤反应中也发挥作用。最近，我们报道干扰素（IFN）激活的中性粒细胞能够释放具有生物活性的肿瘤坏死因子（TNF）相关的凋亡诱导配体（TRAIIL/APO2配体），这种分子对肿瘤和病毒感染的细胞发挥选择性的凋亡活性，并对活化的T淋巴细胞发挥免疫调节功能。在此，我们发现，由 IFN 激活的中性粒细胞在 24 小时内新合成的总 TRAIL 中只有一小部分释放到外部，其余部分保留在细胞内，主要在分泌囊泡和轻膜部分中。我们证明，存在于 IFN 预处理的中性粒细胞中的 TRAIL 细胞内池可快速动员到细胞表面，并且在暴露于促炎介质（例如 TNF-α、脂多糖、甲酰基-甲硫氨酰-亮氨酰-苯丙氨酸、CXC 趋化因子配体 8/白介素-8、不溶性免疫复合物和热休克蛋白 Gp96）后可以分泌。这些不同的促炎激动剂仅起到有效的促分泌分子的作用，因为它们不能增强新鲜分离的中性粒细胞或在有或没有IFN培养的中性粒细胞中的TRAIL mRNA表达或TRAIL从头合成。此外，用促炎介质刺激的经IFN处理的中性粒细胞的上清液比仅用IFN激活的中性粒细胞的上清液更有效地诱导靶细胞凋亡。总的来说，我们的结果揭示了一种新的机制，通过该机制，中性粒细胞释放可溶性 TRAIL 可以被大大放大，并进一步强化了中性粒细胞是肿瘤监测和免疫调节中重要细胞的概念。
Neutrophils are versatile cells, which play a role, not only in inflammatory processes but also in immune and antitumoral responses. Recently, we have reported that interferon (IFN)-activated neutrophils are able to release biologically active tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIIL/APO2 ligand), a molecule exerting selective, apoptotic activities toward tumor and virus-infected cells, as well as immunoregulatory functions on activated T lymphocytes. Herein, we show that only a minor fraction of the total TRAIL, newly synthesized by IFN-activated neutrophils within 24 h, is released outside, the rest being retained intracellularly, mainly in secretory vesicles and light membrane fractions. We demonstrate that the intracellular pool of TRAIL present in IFN-pretreated neutrophils is rapidly mobilizable to the cell surface and can he secreted following exposure to proinflammatory mediators such as TNF-alpha, lipopolysaccharide, formyl-methionyl-leucyl-phenylalanine, CXC chemokine ligand 8/interleukin-8, insoluble immunocomplexes, and heat shock protein Gp96. These various proinflammatory agonists functioned as effective secretagogue molecules only, in that they failed to augment TRAIL mRNA expression or TRAIL de novo synthesis in freshly isolated neutrophils or cultured with or without IFN. In addition, supernatants from IFN-treated neutrophils stimulated with proinflammatory mediators induced the apoptosis of target cells more effectively than supernatants from neutrophils activated with IFNs alone. Collectively, our results uncover a novel mechanism, whereby the release of soluble TRAIL by neutrophils can be greatly amplified and further reinforce the notion that neutrophils are important cells in tumor surveillance and immunomodulation.