IL-8 induces exocytosis of arginase 1 by neutrophil polymorphonuclears in nonsmall cell lung cancer
IL-8 induces exocytosis of arginase 1 by neutrophil polymorphonuclears in nonsmall cell lung cancer
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DOI：
10.1002/ijc.24448
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发表时间：
2009-08-15
影响因子：
6.4
通讯作者：
Barbieri, Ottavia
中科院分区：
文献类型：
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作者：
Rotondo, Rita;Barisione, Gaia;Barbieri, Ottavia
精氨酸酶1(Arg1)通过降解细胞外精氨酸来抑制T细胞的增殖，导致T细胞对CD3/TCR刺激的反应性降低。在人类中，ARG1以不活跃的形式储存在中性粒细胞(PMN)颗粒中，并在释放时被激活。我们研究了中性粒细胞相关的ARG1活性在非小细胞肺癌(NSLC)中的作用，在NSLC中，肿瘤浸润性淋巴细胞在CD3/TCR触发下表现出增殖减少。与健康对照组相比，非小细胞肺癌霍尔患者血浆ARG1水平升高。此外，免疫组织化学显示，与血管内或瘤周PMN相比，肿瘤浸润性PMN显示细胞内ARG1减少，这表明肿瘤微环境在ARG1释放中起作用。事实上，非小细胞肺癌细胞株的培养上清液可以诱导中性粒细胞分泌ARG1。所有(4/4)NSCLC细胞株和ALL(7/7)CD14-细胞株均表达IL-8mRNA，而1株NSCLC细胞株和2例肿瘤标本表达肿瘤坏死因子α。此外，所有NSCLC细胞株都能分泌免疫反应性IL-8，尽管水平不同。IL-8与肿瘤坏死因子α同样有效地促进ARG1的释放，且两种细胞因子协同作用。分泌的ARG1具有生物活性，能分解胞外精氨酸。IL-8基因沉默的NSCLC细胞上清液不能介导中性粒细胞释放ARG1。总之，这些发现证明了IL-8在中性粒细胞分泌ARG1中的作用，并表明至少部分由于非小细胞肺癌细胞分泌IL-8，渗透到非小细胞肺癌的中性粒细胞释放ARG1。这种现象可能导致局部免疫抑制。(C)2009年UICC
Arginase 1 (ARG1) inhibits T-cell proliferation by degrading extracellular arginine, which results in decreased responsiveness of T cells to CD3/TCR stimulation. In humans, ARG1 is stored in inactive form within granules of polymorphonuclear neutrophils (PMNs) and gets activated on release. We studied the role of PMNs-related ARG1 activity in nonsmall cell lung cancer (NSLC), in which tumor-infiltrating lymphocytes showed reduced proliferation in response to CD3/TCR triggering. Patients with NSCLC hall increased ARG1 plasma levels as compared to healthy controls. Furthermore, immunohistochemistry showed that tumor-infiltrating PMNs display reduced intracellular ARG1, in comparison to intravascular or peritumoral PMNs, suggesting a role of tumor microenvironment in ARG1 release. Indeed, supernatants of NSCLC cell lines induced exocytosis of ARG1 from PMNs. All (4/4) NSCLC cell lines and all (7/7) CD14- cell samples from NSCLC expressed interleukin (IL)-8 mRNA, whereas TNF alpha mRNA was expressed by 1 cell line and by 2 tumor specimens. Furthermore, all NSCLC cell lines secreted immunoreactive IL-8, albeit at different levels. IL-8 was as effective as TNF alpha in triggering ARG1 release and the 2 cytokines acted synergistically. Secreted ARG1 was biologically active and catabolized extracellular arginine. The supernatant of IL-8 gene-silenced NSCLC cells did not mediate ARG1 release by PMNs. Altogether these findings demonstrate a role of IL-8 in ARG1 exocytosis by PMNs and indicate that, due at least in part to IL-8 secreted by NSCLC cells, PMNs infiltrating NSCLC release ARG1. This phenomenon could contribute to local immune suppression. (C) 2009 UICC