Targeting the IL-17/IL-6 axis can alter growth of Chronic Lymphocytic Leukemia &ITin vivo&IT/&ITin vitro&IT
Targeting the IL-17/IL-6 axis can alter growth of Chronic Lymphocytic Leukemia &ITin vivo&IT/&ITin vitro&IT
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DOI：
10.1016/j.leukres.2018.01.006
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发表时间：
2018-03-01
影响因子：
2.7
通讯作者：
Gorczynski, Reginald M.
中科院分区：
文献类型：
--
作者：
Zhu, Fang;McCaw, Lindsay;Gorczynski, Reginald M.
肿瘤微环境（TME）对慢性淋巴细胞白血病（CLL）肿瘤B细胞的寿命至关重要。骨髓间充质干细胞（BMMSCs）及其产生的细胞因子包括IL-6是CLL中TME的重要组成部分。我们发现BMMSCs通过IL-6依赖机制支持CLL细胞的体外存活。IL-17在多种细胞中诱导IL-6的产生，在体外CLL细胞和BMMSCs中均增加IL-6的产生。在异种移植CLL小鼠模型中，BMMSCs和BMMSCs培养上清通过IL-6介导的机制增加了CLL细胞的植入，人重组IL-6在体内表现出类似的作用。人重组IL-17处理也通过IL-6介导的机制增加了小鼠的CLL植入。ELISA结果显示，CLL患者血浆中IL-6和IL-17水平均高于健康对照组，且IL-6水平与IL-17水平呈线性相关。需要氟达拉滨化疗的CLL患者IL-6和IL-17表达水平较高，而IgA/IgM水平最低的CLL患者IL-6水平较高，但IL-17水平不高。这些数据暗示了IL-17/IL-6轴在CLL中可能成为治疗靶点的重要作用。
The tumor microenvironment (TME) is critical to the longevity of tumor B cells in chronic lymphocytic leukemia (CLL). Bone marrow mesenchymal stem cells (BMMSCs) and the cytokines they produce including IL-6 are important components of the TME in CLL. We found BMMSCs supported the survival of CLL cells in vitro through an IL-6 dependent mechanism. IL-17 which induces IL-6 generation in a variety of cells increased production of IL-6 both in CLL cells and BMMSCs in vitro. In a xenograft CLL mouse model, BMMSCs and the culture supernatant of BMMSCs increased engraftment of CLL cells through an IL-6 mediated mechanism with human recombinant IL-6 showing similar effects in vivo. Human recombinant IL-17 treatment also increased CLL engraftment in mice through an IL-6 mediated mechanism. Plasma of CLL patients showed elevated levels of both IL-6 and IL-17 by ELISA compared with healthy controls, with levels of IL-6 linearly correlated with IL-17 levels. CLL patients requiring fludarabine based chemotherapy expressed higher levels of IL-6 and IL-17, while CLL patients with the lowest levels of IgA/IgM had higher levels of IL-6, but not IL-17. These data imply an important role for the IL-17/IL-6 axis in CLL which could be therapeutic targets.