Iron regulation of hepatic macrophage TNFalpha expression

Free Radic Biol Med. 2002 Feb 15;32(4):309-13. doi: 10.1016/s0891-5849(01)00772-9.

Abstract

Sustained TNFalpha induction is central to the pathogenesis of chronic liver disease including alcoholic liver disease (ALD). However, molecular understanding of this abnormality at the cellular level remains elusive. Redox regulation of NF-kappaB is critical in the transcriptional control of TNFalpha expression. Evidence supports that increased iron storage in hepatic macrophages (HM) is causally associated with accentuated and sustained NF-kappaB activation in these cells in ALD. Treatment of cultured HM with a lipophilic iron chelator (deferiprone) abrogates LPS-induced NF-kappaB activation. HM from an animal model of ALD have increased nonheme iron content accompanied by increased generation of EPR-detected radicals, NF-kappaB activation, and TNFalpha induction, all of which are normalized by ex vivo treatment of the cells with deferiprone. A moderate increase in the nonheme iron content in HM by erythrophagocytosis, promotes subsequent LPS-stimulated NF-kappaB activation in a hemeoxygenase-dependent manner. Recent evidence also suggests a role of intracellular low molecular weight iron in the early signal transduction for LPS-mediated NF-kappaB activation.

Publication types

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

MeSH terms

  • Animals
  • Electron Spin Resonance Spectroscopy
  • Free Radicals
  • Humans
  • Iron / metabolism*
  • Liver / metabolism*
  • Liver Diseases / metabolism*
  • Macrophages / metabolism*
  • Models, Biological
  • NF-kappa B / metabolism
  • Oxidation-Reduction
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Free Radicals
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Iron