JNK1-STAT3信号通路在T-2毒素诱导RAW264.7细胞凋亡中的作用机制

T-2 toxin in cereals suppresses or stimulates the immune system to weaken or enhance the immune function of animals, thus, will influence the occurrence of animal diseases. Our previous study has shown that T-2 toxin in RAW264.7 cells could activate JNK1-STAT3 and STAT1 pathways simultaneously. Moreover, STAT1 could stimulate cell apoptosis, whereas JNK1-STAT3 was able to inhibit the cell apoptosis induced by T-2 toxin. However, the mechanism underlying the balance of JNK-STAT3 and STAT1 activation to regulate the cell survival and cell apoptosis is still not clear. Our recent studies have further shown that AKT and ITCH regulated the STAT1/3 activation; T-2 toxin in different doses led to the different STAT3 phosphorylation levels, suggesting the potential signal pathways and the threshold dose of T-2 toxin are critical regulators in this balance. In this project, we aim at using RAW264.7 cell line as the model, to study the potential signal pathways in the regulation of the balance of JNK1-STAT3 and STAT1 activation, and to elucidate the mechanism of cell apoptosis and cell survival development; meanwhile, we will study the potential role of threshold dose of T-2 toxin in this balance. This project will provide a new molecular target for the underlying of the mechanism of immunosuppressant and immune stimulation, thus will provide further scientific theory for animal disease prevention and control.

谷物中T-2毒素可抑制或刺激动物免疫系统，削弱或增强机体免疫机能，进而影响动物疫病的发生。前期研究我们报道：T-2毒素可同时激活STAT1和JNK1-STAT3通路；STAT1促进细胞凋亡，而JNK1-STAT3通路抑制细胞凋亡。然而，调控细胞凋亡、存活走向的STAT1和JNK1-STAT3通路平衡的分子机制仍不清楚。本项目组进一步研究发现：信号通路AKT和ITCH能调控STAT1/3表达；不同浓度T-2毒素引起STAT3磷酸化水平差异，预示潜在信号通路和毒素浓度阈值是调控此通路平衡的重要因素。在此基础上，本项目以RAW264.7细胞为模型，①深层解析维持JNK1-STAT3和STAT1通路平衡的关键因素，阐明T-2毒素诱导细胞凋亡、存活走向的信号传导机理；②明确毒素剂量阈值在细胞凋亡、存活平衡中的作用。本项目为毒素的免疫抑制和刺激形成机理提供新的分子靶点，也为动物疫病防控提供理论依据。

T-2毒素具有强免疫毒性，感染动物后可引起免疫机能下降。进一步研究发现T-2毒素具有（正负）免疫调控作用。然而，其潜在分子机制并未研究清楚。本项目从信号通路、自噬、剂量与代谢、免疫逃避等多角度综合阐释了T-2毒素的免疫调控机制。研究发现T-2毒素可启动自噬通路调控免疫调控功能。而免疫逃避机制为调控T-2毒素介导免疫毒性的一个潜在新机制，可通过JNK/STAT信号调控免疫逃避机制密切相关的蛋白IFN-gama、TLR-4的变化，改变细胞免疫微环境，使得细胞不能抵御毒素的危害。而这当中，缺氧诱导因子HIF-1a发挥了重要作用，启动免疫逃避使得细胞存活。T-2毒素代谢物在免疫毒性中不占主导地位，并存在一个剂量范围8-18 nM调控细胞的凋亡与存活。转录因子AKNA受PKA/CREB和NF-kB调为T-2毒素介导免疫毒性的下游分子靶标。此外，T-2毒素通过参与p16/Rb信号通路诱导ROS介导的氧化应激和p53与caspase级联相互作用的DNA损伤，导致细胞凋亡。而DNA甲基化是T-2毒素免疫毒性中的另一个关注点。T-2毒素可迅速增加DNA甲基转移酶（DNMT1、DNMT3A）的水平，进一步调节T-2毒素刺激后RASSF4蛋白表达，并激活其下游途径，促进细胞凋亡机制中发挥重要作用。本研究为单端孢霉烯族毒素免疫调控机制提供进一步的数据，为动物疫病防控提供理论依据。

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