Iron activates NF-κB in Kupffer cells

Hongyun She, Shigang Xiong, Min Lin, Ebrahim Zandi, Cecilia R Giulivi, Hidekazu Tsukamoto

Research output: Contribution to journalArticle

93 Scopus citations

Abstract

Iron exacerbates various types of liver injury in which nuclear factor (NF)-κB-driven genes are implicated. This study tested a hypothesis that iron directly elicits the signaling required for activation of NF-κB and stimulation of tumor necrosis factor (TNF)-α gene expression in Kupffer cells. Addition of Fe2- but not Fe3+ (∼-5-50 μM) to cultured rat Kupffer cells increased TNF-α. release and TNF-α. promoter activity in a NF-κB-dependent manner. Cu+ but not Cu2+ stimulated TNF-α protein release and promoter activity but with less potency. Fe2+ caused a disappearance of the cytosolic inhibitor κBα, a concomitant increase in nuclear p65 protein, and increased DNA binding of p50/p50 and p65/p50 without affecting activator protein-1 binding. Addition of Fe2- to the cells resulted in an increase in electron paramagnetic resonance-detectable ·OH peaking at 15 min, preceding activation of NF-κB but coinciding with activation of inhibitor κB kinase (IKK) but not c-Jun NH2-terminal kinase. In conclusion, Fe2- serves as a direct agonist to activate IKK, NF-κB, and TNF-α promoter activity and to induce the release of TNF-α protein by cultured Kupffer cells in a redox status-dependent manner. We propose that this finding offers a molecular basis for iron-mediated accentuation of TNF-α-dependent liver injury.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume283
Issue number3 46-3
StatePublished - Sep 2002
Externally publishedYes

Keywords

  • Electron paramagnetic resonance
  • Free radical
  • Inhibitor κB kinase
  • Nuclear factor-κB
  • Promoter
  • Tumor necrosis factor-α

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology

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