Induction of competing apoptotic and survival signaling pathways in the macrophage by the ribotoxic trichothecene deoxynivalenol.
Induction of competing apoptotic and survival signaling pathways in the macrophage by the ribotoxic trichothecene deoxynivalenol.
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DOI：
10.1093/toxsci/kfi234
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发表时间：
2005-09
期刊：
影响因子：
--
通讯作者：
Hui-Ren Zhou;Z. Islam;J. Pestka
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文献类型：
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作者：
Hui-Ren Zhou;Z. Islam;J. Pestka
脱氧雪腐镰刀菌烯醇（DON）和其他核糖毒性的二孢霉素分别通过上调基因表达和细胞凋亡引起白细胞中的免疫刺激和抑制。本研究的目的是检验MAPK介导DON暴露的巨噬细胞凋亡和存活的假设。在部分抑制翻译的浓度下，DON在15分钟内诱导RAW 264.7巨噬细胞中p38和ERK 1/2丝裂原活化蛋白激酶的磷酸化，并且这些作用持续长达3小时。DON暴露的细胞表现出明显的caspase 3依赖的DNA片段化后6小时，这是抑制和减弱p38抑制剂SB 203580和ERK抑制剂PD 98059，分别。DON容易诱导p53的磷酸化和活性，并且这可被SB 203580所替代。DON暴露诱发BAX易位到线粒体和相应的细胞色素C释放，但不改变线粒体膜电位。P53抑制剂PFT alpha降低了DON诱导的p53磷酸化和p53结合活性。此外，PFT α和p53 siRNA转染抑制了DON诱导的caspase-3活性和随后的DNA片段化。与p53激活同时，DON激活两个抗凋亡存活途径，如ERK依赖性p90 Rsk和AKT激活所证明的。综上所述，结果表明DON在巨噬细胞中启动竞争性凋亡（p38/p53/Bax/线粒体/Caspase-3）和存活（ERK/AKT/p90 Rsk/Bad）途径。
Deoxynivalenol (DON) and other ribotoxic trichothecenes cause immune stimulation and suppression in leukocytes by upregulating gene expression and apoptosis, respectively. The purpose of this study was to test the hypothesis that MAPKs mediate both apoptosis and survival in DON-exposed macrophages. At concentrations which partially inhibit translation, DON induced phosphorylation of p38 and ERK 1/2 mitogen activated protein kinases within 15 min in RAW 264.7 macrophages and these effects lasted up to 3 h. DON-exposed cells exhibited marked caspase 3-dependent DNA fragmentation after 6 h which was suppressed and attenuated by the p38 inhibitor SB203580 and ERK inhibitor PD98059, respectively. DON readily induced the phosphorylation and activity of p53 and this was inhibitable by SB203580. DON exposure evoked BAX translocation to mitochondria and corresponding cytochrome C release but did not alter mitochondrial membrane potential. The p53 inhibitor PFTalpha reduced both DON-induced phosphorylation of p53 and p53 binding activity. Moreover, both PFTalpha and p53 siRNA transfection suppressed DON-induced caspase-3 activity and subsequent DNA fragmentation. Concurrent with p53 activation, DON activated two anti-apoptotic survival pathways as evidenced by both ERK-dependent p90 Rsk and AKT activation. Taken together, the results indicate that DON initiates competing apoptotic (p38/p53/Bax/Mitochondria/Caspase-3) and survival (ERK/AKT/p90Rsk/Bad) pathways in the macrophage.