Liu Xianglian, Huang Deyu, Guo Pu, Wu Qinghua, Dai Menghong, Cheng Guyue, Hao Haihong, Xie Shuyu, Yuan Zonghui, Wang Xu
National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, China.
MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Wuhan, China.
Toxicology. 2017 Dec 1;392:81-95. doi: 10.1016/j.tox.2017.10.013. Epub 2017 Oct 25.
Chronic exposure to low dose of T-2 toxin causes growth retardation and reduced body weight, resulting in economic losses. Excessive inflammatory cytokines and GH deficiency are important mechanisms that contribute to growth inhibition induced by T-2 toxin. However, the regulation of the inflammatory cytokines expecially IL-6, IL-1β, and TNF-α induced by T-2 toxin still remained unclear. The new transcription factor AKNA, belonging to AT-hook protein family, is closely associated with inflammation. However, it was unclear how AKNA regulate the expression of inflammatory cytokines, and there was no report on the role of AKNA in T-2 toxin mediated toxicity. Here, we investigated the role of AKNA in T-2 toxin-mediated inflammatory response and GH deficiency and the signal transduction pathway of AKNA. We showed that AKNA regulated by PKA/CREB and NF-κB pathway is a novel downstream molecular target in T-2 toxin-mediated inflammation and GH deficiency. T-2 toxin activates the PKA/CREB and NF-κB/p65 pathways, thereby promoting the direct binding of phospho-CREB and phospho-p65 to the AKNA promoter, thus inhibiting AKNA expression. GH and inflammatory cytokines (TNF-α, IL-1β, and IL-6) expression were significantly downregulated after AKNA silencing. Furthermore, the expression of differential genes induced by T-2 toxin in the rat pituitary was further confirmed by acute toxicity tests in rats, which was consistent with the results in GH3 cells. By histopathological analysis, we confirmed the pituitary might be a novel direct target organ of T-2 toxin. These findings provided new insights into the significant role of AKNA in T-2 toxin-induced inflammatory response and growth inhibition.
长期暴露于低剂量的T-2毒素会导致生长发育迟缓、体重减轻，从而造成经济损失。过量的炎性细胞因子和生长激素缺乏是T-2毒素诱导生长抑制的重要机制。然而，T-2毒素诱导的炎性细胞因子尤其是白细胞介素-6（IL-6）、白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNF-α）的调控机制仍不清楚。新型转录因子AKNA属于AT钩蛋白家族，与炎症密切相关。然而，尚不清楚AKNA如何调节炎性细胞因子的表达，且尚无关于AKNA在T-2毒素介导的毒性作用中作用的报道。在此，我们研究了AKNA在T-2毒素介导的炎症反应和生长激素缺乏中的作用以及AKNA的信号转导途径。我们发现，由蛋白激酶A（PKA）/环磷腺苷反应元件结合蛋白（CREB）和核因子κB（NF-κB）途径调控的AKNA是T-2毒素介导的炎症和生长激素缺乏中的一个新的下游分子靶点。T-2毒素激活PKA/CREB和NF-κB/p65途径，从而促进磷酸化CREB和磷酸化p65与AKNA启动子的直接结合，进而抑制AKNA表达。AKNA沉默后，生长激素及炎性细胞因子（TNF-α、IL-1β和IL-6）的表达显著下调。此外，通过大鼠急性毒性试验进一步证实了T-2毒素在大鼠垂体中诱导的差异基因表达，这与在GH3细胞中的结果一致。通过组织病理学分析，我们证实垂体可能是T-2毒素的一个新的直接靶器官。这些发现为AKNA在T-2毒素诱导的炎症反应和生长抑制中的重要作用提供了新的见解。
