Ferritin heavy chain upregulation by NF-kappaB inhibits TNFalpha-induced apoptosis by suppressing reactive oxygen species

Cell. 2004 Nov 12;119(4):529-42. doi: 10.1016/j.cell.2004.10.017.

Abstract

During inflammation, NF-kappaB transcription factors antagonize apoptosis induced by tumor necrosis factor (TNF)alpha. This antiapoptotic activity of NF-kappaB involves suppressing the accumulation of reactive oxygen species (ROS) and controlling the activation of the c-Jun N-terminal kinase (JNK) cascade. However, the mechanism(s) by which NF-kappaB inhibits ROS accumulation is unclear. We identify ferritin heavy chain (FHC)--the primary iron storage factor--as an essential mediator of the antioxidant and protective activities of NF-kappaB. FHC is induced downstream of NF-kappaB and is required to prevent sustained JNK activation and, thereby, apoptosis triggered by TNFalpha. FHC-mediated inhibition of JNK signaling depends on suppressing ROS accumulation and is achieved through iron sequestration. These findings establish a basis for the NF-kappaB-mediated control of ROS induction and identify a mechanism by which NF-kappaB suppresses proapoptotic JNK signaling. Our results suggest modulation of FHC or, more broadly, of iron metabolism as a potential approach for anti-inflammatory therapy.

Publication types

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

MeSH terms

  • Apoptosis / drug effects*
  • Ferritins / metabolism*
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • Inflammation / metabolism
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Protein-Serine-Threonine Kinases / pharmacology*
  • Reactive Oxygen Species / metabolism*
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Up-Regulation

Substances

  • Reactive Oxygen Species
  • Tumor Necrosis Factor-alpha
  • Ferritins
  • Protein-Serine-Threonine Kinases
  • JNK Mitogen-Activated Protein Kinases
  • NF-kappa B kinase
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases