Pharmacologic IKK/NF-κB inhibition causes antigen presenting cells to undergo TNFα dependent ROS-mediated programmed cell death

Sci Rep. 2014 Jan 10:4:3631. doi: 10.1038/srep03631.

Abstract

Monocyte-derived antigen presenting cells (APC) are central mediators of the innate and adaptive immune response in inflammatory diseases. As such, APC are appropriate targets for therapeutic intervention to ameliorate certain diseases. APC differentiation, activation and functions are regulated by the NF-κB family of transcription factors. Herein, we examined the effect of NF-κB inhibition, via suppression of the IκB Kinase (IKK) complex, on APC function. Murine bone marrow-derived macrophages and dendritic cells (DC), as well as macrophage and DC lines, underwent rapid programmed cell death (PCD) after treatment with several IKK/NF-κB inhibitors through a TNFα-dependent mechanism. PCD was induced proximally by reactive oxygen species (ROS) formation, which causes a loss of mitochondrial membrane potential and activation of a caspase signaling cascade. NF-κB-inhibition-induced PCD of APC may be a key mechanism through which therapeutic targeting of NF-κB reduces inflammatory pathologies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antigen-Presenting Cells / cytology*
  • Apoptosis / physiology*
  • Caspase 8 / metabolism
  • Cell Line
  • Enzyme Activation
  • I-kappa B Kinase / antagonists & inhibitors*
  • MAP Kinase Kinase 4 / metabolism
  • Macrophages / cytology
  • Macrophages / drug effects
  • Mice
  • NF-kappa B / antagonists & inhibitors*
  • Reactive Oxygen Species / metabolism*
  • Tumor Necrosis Factor-alpha / physiology*

Substances

  • NF-kappa B
  • Reactive Oxygen Species
  • Tumor Necrosis Factor-alpha
  • I-kappa B Kinase
  • MAP Kinase Kinase 4
  • Caspase 8