Cellular and molecular mechanisms for immune modulation by deoxynivalenol and other trichothecenes: unraveling a paradox
Cellular and molecular mechanisms for immune modulation by deoxynivalenol and other trichothecenes: unraveling a paradox
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DOI：
10.1016/j.toxlet.2004.04.023
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发表时间：
2004-10-10
影响因子：
3.5
通讯作者：
Chung, YJ
中科院分区：
文献类型：
--
作者：
Pestka, JJ;Zhou, HR;Chung, YJ
免疫系统的巨噬细胞、T细胞和B细胞是脱氧雪腐镰刀菌烯醇（DON）和其它二孢霉烯类真菌毒素的中心靶标，其可以是免疫刺激性的或免疫抑制性的，这取决于剂量、暴露频率和功能性免疫测定的时间。值得注意的是，低剂量的二孢噻吩暴露在转录和转录后上调细胞因子、趋化因子和炎性基因的表达，同时伴有免疫刺激，而高剂量的暴露促进白细胞凋亡，同时伴有免疫抑制。DON和其他的二聚体，通过一种称为核糖毒性应激反应的机制，与核糖体结合并迅速激活促分裂原活化蛋白激酶（MAPK）。后者是与免疫应答和细胞凋亡相关的下游信号事件的重要转换器。使用克隆的巨噬细胞，我们的实验室已经确定了两个关键的上游传感器的DON诱导的MAPK激活。其中一种是双链RNA激活蛋白激酶（PKR），这是一种广泛表达的丝氨酸/苏氨酸蛋白激酶，可被dsRNA、干扰素和其他试剂激活。第二个传感器是造血细胞激酶（Hck），一种非受体相关的Src家族激酶。抑制剂和基因沉默研究表明，Hck和PKR在DON诱导的基因表达和细胞凋亡中发挥作用。未来的研究应集中在这些激酶和青蒿素毒性之间的分子联系。(C)2004年ILSI。由Elsevier爱尔兰有限公司出版。保留所有权利。
Macrophages, T cells, and B cells of the immune system are central targets of deoxynivalenol (DON) and other trichothecenes-mycotoxins that can be immunostimulatory or immunosuppressive depending on dose, exposure frequency and timing of functional immune assay. Notably, low dose trichothecene exposure transcriptionally and post-transcriptionally upregulates expression of cytokines, chemokines and inflammatory genes with concurrent immune stimulation, whereas high dose exposure promotes leukocyte apoptosis with concomitant immune suppression. DON and other trichothecenes, via a mechanism known as the ribotoxic stress response, bind to ribosomes and rapidly activate mitogen-activated protein kinases (MAPKs). The latter are important transducers of downstream signaling events related to immune response and apoptosis. Using cloned macrophages, our laboratory has identified two critical upstream transducers of DON-induced MAPK activation. One transducer is double-stranded RNA-(dsRNA)-activated protein kinase (PKR), a widely-expressed serine/theonine protein kinase that can be activated by dsRNA, interferon, and other agents. The second transducer is hematopoetic cell kinase (Hck), a non-receptor associated Src family kinase. Inhibitors and gene silencing studies have revealed that Hck and PKR play roles in DON induced gene expression and apoptosis. Future studies should focus on the molecular linkages between these kinases and trichothecene toxicity. (C) 2004 ILSI. Published by Elsevier Ireland Ltd. All rights reserved.