TAK1 Mediates ROS Generation Triggered by the Specific Cephalosporins through Noncanonical Mechanisms

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 H2O2. 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.

Keywords: antibacterial agents; macrophages; reactive oxygen species (ROS); transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1).

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Blotting, Western
  • Cefotaxime / pharmacology
  • Cell Survival / drug effects
  • Cephalosporins / pharmacology*
  • MAP Kinase Kinase Kinase 5 / metabolism
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism*
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases / metabolism
  • Oxidative Stress / drug effects
  • RAW 264.7 Cells
  • Reactive Oxygen Species / metabolism*
  • Signal Transduction / drug effects


  • Anti-Bacterial Agents
  • Cephalosporins
  • Reactive Oxygen Species
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 5
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Map3k5 protein, mouse
  • Cefotaxime