Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
Int J Mol Sci. 2020 Dec 14;21(24):9497. doi: 10.3390/ijms21249497.
It is known that a wide variety of antibacterial agents stimulate generation of reactive oxygen species (ROS) in mammalian cells. However, its mechanisms are largely unknown. In this study, we unexpectedly found that transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) is involved in the generation of mitochondrial ROS (mtROS) initiated by cefotaxime (CTX), one of specific antibacterial cephalosporins that can trigger oxidative stress-induced cell death. TAK1-deficient macrophages were found to be sensitive to oxidative stress-induced cell death stimulated by HO. Curiously, however, TAK1-deficient macrophages exhibited strong resistance to oxidative stress-induced cell death stimulated by CTX. Microscopic analysis revealed that CTX-induced ROS generation was overridden by knockout or inhibition of TAK1, suggesting that the kinase activity of TAK1 is required for CTX-induced ROS generation. Interestingly, pharmacological blockade of the TAK1 downstream pathways, such as nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, did not affect the CTX-induced ROS generation. In addition, we observed that CTX promotes translocation of TAK1 to mitochondria. Together, these observations suggest that mitochondrial TAK1 mediates the CTX-induced mtROS generation through noncanonical mechanisms. Thus, our data demonstrate a novel and atypical function of TAK1 that mediates mtROS generation triggered by the specific cephalosporins.
众所周知，多种抗菌剂会刺激哺乳动物细胞中活性氧（ROS）的产生。然而，其机制在很大程度上尚不清楚。在这项研究中，我们意外地发现，转化生长因子-β（TGF-β）激活激酶 1（TAK1）参与了头孢噻肟（CTX）引发的线粒体 ROS（mtROS）的产生，CTX 是一种特定的抗菌头孢菌素，可引发氧化应激诱导的细胞死亡。发现 TAK1 缺陷型巨噬细胞对 HO 刺激的氧化应激诱导的细胞死亡敏感。然而，令人好奇的是，TAK1 缺陷型巨噬细胞对 CTX 刺激的氧化应激诱导的细胞死亡表现出强烈的抗性。显微镜分析表明，CTx 诱导的 ROS 生成被 TAK1 的敲除或抑制所掩盖，这表明 TAK1 的激酶活性是 CTX 诱导的 ROS 生成所必需的。有趣的是，TAK1 下游途径（如核因子-κB（NF-κB）和丝裂原活化蛋白激酶（MAPK）途径）的药理学阻断并不影响 CTX 诱导的 ROS 生成。此外，我们观察到 CTX 促进 TAK1 向线粒体的易位。总之，这些观察结果表明，线粒体 TAK1 通过非典型机制介导 CTX 诱导的 mtROS 生成。因此，我们的数据表明 TAK1 具有介导特定头孢菌素触发的 mtROS 生成的新型和非典型功能。
