Role of GRP78/BiP Degradation and ER Stress in Deoxynivalenol-Induced Interleukin-6 Upregulation in the Macrophage
Role of GRP78/BiP Degradation and ER Stress in Deoxynivalenol-Induced Interleukin-6 Upregulation in the Macrophage
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DOI：
10.1093/toxsci/kfp060
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发表时间：
2009-06-01
影响因子：
3.8
通讯作者：
Pestka, James J.
中科院分区：
文献类型：
--
作者：
Shi, Yuhui;Porter, Katie;Pestka, James J.
在小鼠中，白孢霉烯真菌毒素脱氧雪腐镰刀菌烯醇（DON）诱导白细胞介素-6（IL-6）和其他促炎细胞因子的系统表达。本研究的目的是检验DON在能够驱动IL-6基因表达的小鼠巨噬细胞中触发内质网（ER）应激反应的假设。DON浓度高达5000 ng/ml。对腹膜细胞无细胞毒性。然而，DON显着降低蛋白质水平，但不是葡萄糖调节蛋白（GRP）78（BiP），一种已知介导ER应激的伴侣蛋白的mRNA水平。抑制剂研究表明，DON诱导的GRP 78降解是组织蛋白酶和钙蛋白酶依赖性的，但不依赖于蛋白酶体。RNAi介导的GRP 78敲低导致IL-6基因表达增加，表明该分子伴侣具有潜在的下调作用。GRP 78对调节两种转录因子X-box结合蛋白1（XBP 1）和激活转录因子6（ATF 6）至关重要，这两种转录因子结合cAMP反应元件（CRE）并驱动CRE依赖性基因如IL-6的表达。发现DON暴露增加IRE 1 α蛋白、其修饰产物剪接的XBP 1 mRNA和XBP 1蛋白以及ATF 6。敲低ATF 6而非XBP 1可部分抑制巨噬细胞中DON诱导的IL-6表达。另外三种蓖麻毒素（satratoxin G，roridin，T-2毒素）和核糖体抑制蛋白蓖麻毒素也被发现诱导GRP 78降解，这表明其他翻译抑制剂可能引起ER应激。总之，这些数据表明，在巨噬细胞中，DON诱导GRP 78降解并引起ER应激反应，这可能部分地有助于DON诱导的IL-6基因表达。
The trichothecene mycotoxin deoxynivalenol (DON) induces systemic expression of the interleukin-6 (IL-6) and other proinflammatory cytokines in the mouse. The purpose of this study was to test the hypothesis that DON triggers an endoplasmic reticulum (ER) stress response in murine macrophages capable of driving IL-6 gene expression. DON at concentrations up 5000 ng/ml. was not cytotoxic to peritoneal cells. However, DON markedly decreased protein levels but not the mRNA levels of glucose-regulated protein (GRP) 78 (BiP), a chaperone known to mediate ER stress. Inhibitor studies suggested that DON-induced GRP78 degradation was cathepsin and calpain dependent but was proteosome-independent. RNAi-mediated knockdown of GRP78 resulted in increased IL-6 gene expression indicating a potential downregulatory role for this chaperone. GRP78 is critical to the regulation of the two transcription factors, X-box binding protein 1 (XBP1) and activating transcription factor 6 (ATF6), which bind to cAMP-response element (CRE) and drive expression of CRE-dependent genes such as IL-6. DON exposure was found to increase IRE1 alpha protein, its modified products spliced XBP1 mRNA and XBP1 protein as well as ATF6. Knockdown of ATF6 but not XBP1 partially inhibited DON-induced IL-6 expression in the macrophages. Three other trichothecenes (satratoxin G, roridin, T-2 toxin) and the ribosome inhibitory protein ricin were also found to induce GRP78 degradation suggesting that other translation inhibitors might evoke ER stress. Taken together, these data suggest that in the macrophage DON induces GRP78 degradation and evokes an ER stress response that could contribute, in part, to DON-induced IL-6 gene expression.