Extracellular histones trigger oxidative stress-dependent induction of the NF-kB/CAM pathway via TLR4 in endothelial cells

J Physiol Biochem. 2023 May;79(2):251-260. doi: 10.1007/s13105-022-00935-z. Epub 2022 Dec 5.


Extracellular histones have been reported to aggravate different pathophysiological processes by increasing vascular permeability, coagulopathy, and inflammation. In the present study, we elucidate how extracellular histones (10-100 µg/mL) concentration dependently increase cytosolic reactive oxygen species (ROS) production using human umbilical vein endothelial cells (HUVECs). Furthermore, we identify cyclooxygenase (COX) and NADPH oxidase (NOX) activity as sources of ROS production in extracellular histone-treated HUVEC. This COX/NOX-mediated ROS production is also involved in enhanced NF-kB activity and cell adhesion molecules (VCAM1 and ICAM1) expression in histone-treated HUVEC. Finally, by using different toll-like receptor (TLR) antagonists, we demonstrate the role of TLR4 in CAMs overexpression triggered by extracellular histones in endothelial cells. In conclusion, our data suggest that through TLR4 signaling, extracellular histones increase endothelial cell activation, a mechanism involving increased COX- and NOX-mediated ROS. These findings increase our understanding on how extracellular histones enhance systemic inflammatory responses in diseases in which histone release occurs as part of the pathological processes.

Keywords: Endothelium; Extracellular histones; Inflammation.

MeSH terms

  • Cell Adhesion Molecules
  • Histones*
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • NADPH Oxidases / metabolism
  • NF-kappa B* / metabolism
  • Oxidative Stress
  • Reactive Oxygen Species / metabolism
  • Toll-Like Receptor 4 / metabolism


  • Histones
  • NF-kappa B
  • Reactive Oxygen Species
  • Toll-Like Receptor 4
  • Cell Adhesion Molecules
  • NADPH Oxidases
  • TLR4 protein, human