National Reference Laboratory of Veterinary Drug Residues (Huazhong Agricultural University)/Ministry of Agriculture Key Laboratory for the Detection of Veterinary Drug Residues in Foods, Huazhong Agricultural University, Wuhan, Hubei 430070, China.
Toxicol Sci. 2012 Jun;127(2):412-24. doi: 10.1093/toxsci/kfs106. Epub 2012 Mar 27.
Deoxynivalenol (DON) and T-2 toxin commonly affect cells of the immune system and cause inflammation and apoptosis. Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway is highly associated with inflammatory process and apoptosis and is worth investigating its role when cells were exposed to trichothecenes. The results showed that DON and T-2 upregulated the messenger RNA (mRNA) expressions of interleukin (IL)-6, IL-1β, tumor necrosis factor-α, JAK1-2, STAT1-3, and suppressors of cytokine signaling members and activated the tyrosine phosphorylation of STAT1 and STAT3 with a dose-dependent manner in RAW264.7 cells. AG490 and Stattic, the specific inhibitors of JAK/STAT pathway, blocked the STAT1 and STAT3 tyrosine phosphorylation and decreased the gene expressions of proinflammatory cytokines induced by trichothecenes. Interestingly, the time when the mRNA levels of STAT1 and STAT3 were significantly upregulated was at 12 h, which was much later than the time when mitogen-activated protein kinase was activated, indicating that STATs might be the downstream targets of the trichothecenes. With the intervention of AG490 and Stattic, DON and T-2 toxin induced apoptosis in a strengthened way, with the loss of mitochondrial membrane potential and the decrease ratios of the B-cell leukemia/lymphoma 2 (Bcl-2)/bcl-2-associated X (Bax) and B-cell lymphoma-extra large (Bcl-xL)/Bax. After exposing to DON and T-2 toxin, cells exhibited G2/M and G0/G1 phase arrest, respectively. The increased mRNA expressions of STAT target genes p21 and cyclin D1 for DON and the increases in p21 mRNA and the decreases in cyclin D1 for T-2 toxin were observed. These results demonstrated for the first time that the activation of JAK/STAT might be a critical mediator to induce the inflammatory response and apoptosis in macrophage in response to trichothecenes.
脱氧雪腐镰刀菌烯醇（DON）和 T-2 毒素通常会影响免疫系统细胞，引起炎症和细胞凋亡。Janus 激酶/信号转导和转录激活因子（JAK/STAT）通路与炎症过程和细胞凋亡密切相关，当细胞暴露于单端孢霉烯族毒素时，研究其作用具有重要意义。结果表明，DON 和 T-2 以剂量依赖的方式上调了 RAW264.7 细胞中白细胞介素（IL）-6、IL-1β、肿瘤坏死因子-α、JAK1-2、STAT1-3 和细胞因子信号转导抑制因子成员的信使 RNA（mRNA）表达，并激活 STAT1 和 STAT3 的酪氨酸磷酸化。AG490 和 Stattic，即 JAK/STAT 通路的特异性抑制剂，阻断了 STAT1 和 STAT3 的酪氨酸磷酸化，并降低了单端孢霉烯族毒素诱导的促炎细胞因子的基因表达。有趣的是，STAT1 和 STAT3 的 mRNA 水平显著上调的时间是在 12 h，这比丝裂原活化蛋白激酶被激活的时间要晚得多，这表明 STATs 可能是单端孢霉烯族毒素的下游靶标。通过干预 AG490 和 Stattic，DON 和 T-2 毒素以增强的方式诱导细胞凋亡，伴随着线粒体膜电位的丧失以及 B 细胞白血病/淋巴瘤 2（Bcl-2）/Bcl-2 相关 X（Bax）和 B 细胞淋巴瘤-extra large（Bcl-xL）/Bax 的比值降低。在暴露于 DON 和 T-2 毒素后，细胞分别出现 G2/M 和 G0/G1 期阻滞。观察到 DON 的 STAT 靶基因 p21 和细胞周期蛋白 D1 的 mRNA 表达增加，以及 T-2 毒素的 p21 mRNA 增加和细胞周期蛋白 D1 减少。这些结果首次表明，JAK/STAT 的激活可能是诱导巨噬细胞对单端孢霉烯族毒素产生炎症反应和细胞凋亡的关键介质。
