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

Jeremy S. Tilstra, Daniel F. Gaddy, Jing Zhao, Shaival H. Davé, Laura J. Niedernhofer, Scott E. Plevy, Paul D. Robbins

Research output: Contribution to journalArticle

15 Scopus citations

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.

Original languageEnglish (US)
Article number3631
JournalScientific reports
Volume4
DOIs
StatePublished - Jan 10 2014
Externally publishedYes

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