Natural killer cell mediated cytotoxicity of tumor cells initiated by neem leaf preparation is associated with CD40-CD40L-mediated endogenous production of interleukin-12
Natural killer cell mediated cytotoxicity of tumor cells initiated by neem leaf preparation is associated with CD40-CD40L-mediated endogenous production of interleukin-12
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DOI：
10.1016/j.humimm.2007.08.002
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发表时间：
2007-10-01
期刊：
影响因子：
2.7
通讯作者：
Baral, Rathindranath
中科院分区：
文献类型：
--
作者：
Bose, Anamika;Baral, Rathindranath
研究发现印度楝叶制剂（NLP）可激活自然杀伤（NK）细胞(CD56(+)CD3(-))，增强其对肿瘤细胞的细胞毒能力，并刺激健康个体和头颈部鳞状细胞癌患者巨噬细胞释放白细胞介素-12 （IL-12）。NLP上调细胞毒性（CD16（+）和CD56(dim)） NK细胞，且NLP刺激的外周血单核细胞对NK敏感的K562细胞的细胞毒性在IL-12中和后显著降低。nk介导的细胞毒性表现为il -12依赖性穿孔蛋白颗粒酶B系统细胞内表达的上调。此外，使用穿孔素抑制剂concanamycin A后，NK细胞毒功能被消除，而使用Fas抑制剂brefeldin A则没有，这证实了穿孔素颗粒酶B系统的参与。此外，NLP上调CD14（+）单核细胞中CD40和CD56（+）淋巴细胞中CD40L的表达。在nlp刺激的外周血单个核细胞培养中，CD40和CD40L的中和导致NK细胞IL-12释放和细胞毒性的显著下调，表明CD40-CD40L相互作用在观察到的功能中起作用。nlp诱导IL-12释放从而诱导NK细胞细胞毒性的信号是通过激活p38MAPK通路介导的，而不是通过ERK1/2信号通路介导的。总的来说，结果表明NLP通过cd40 - cd40l介导的内源性IL-12产生NK细胞的细胞毒性，IL-12对穿孔依赖的肿瘤细胞毒性有关键的控制作用。(c) 2007年美国组织相容性和免疫遗传学学会。Elsevier Inc.出版。版权所有。
Neem leaf preparation (NLP) was found to activate natural killer (NK) cells (CD56(+)CD3(-)) to enhance their cytotoxic ability to tumor cells and stimulate the release of interleukin-12 (IL-12) from macrophages from healthy individuals and head-and-neck squamous cell carcionoma patients. NLP upregulated cytotoxic (CD16(+) and CD56(dim)) NK cells, and the cytotoxicity of NK-sensitive K562 cells by NLP-stimulated peripheral blood mononuclear cells decreased significantly after IL-12 neutralization. This NK-mediated cytotoxicity was manifest by upregulation of IL-12-dependent intracellular expression of the perforin-granzyme B system. Moreover, NK cytotoxic function was abolished after use of concanamycin A, a perforin inhibitor, but not by brefeldin A, a Fas inhibitor, confirming the participation of the perforin-granzyme B system. In addition NLP upregulated the expression of CD40 in CD14(+) monocytes and CD40L in CD56(+) lymphocytes. Neutralization of CD40 and CD40L in NLP-stimulated peripheral blood mononuclear cells culture resulted in significant downregulation of IL-12 release and cytotoxicity of NK cells, demonstrating the role of a CD40-CD40L interaction in the observed functions. Signals involved in the NLP-induced release of IL-12, and thereby induction of NK cell cytotoxicity, are mediated by activating p38MAPK pathway, but not through the ERK1/2 signaling pathway. Overall the results suggest that NLP effects NK cellular cytotoxicity by CD40-CD40L-mediated endogenous production of IL-12, which critically controls perforin-dependent tumor cell cytotoxicity. (c) 2007 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.