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Am J Physiol Gastrointest Liver Physiol 283: G719-G726, 2002; doi:10.1152/ajpgi.00108.2002
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Vol. 283, Issue 3, G719-G726, September 2002

Iron activates NF-kappa B in Kupffer cells

Hongyun She1, Shigang Xiong1, Min Lin1, Ebrahim Zandi2, Cecilia Giulivi3, and Hidekazu Tsukamoto1

1 Departments of Pathology and 2 Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033-9141; and 3 Department of Chemistry, University of Minnesota, Duluth, Minnesota 55812

10.1152/ajpgi.00108. 2002.--- Iron exacerbates various types of liver injury in which nuclear factor (NF)-kappa B-driven genes are implicated. This study tested a hypothesis that iron directly elicits the signaling required for activation of NF-kappa B and stimulation of tumor necrosis factor (TNF)-alpha gene expression in Kupffer cells. Addition of Fe2+ but not Fe3+ (~5-50 µM) to cultured rat Kupffer cells increased TNF-alpha release and TNF-alpha promoter activity in a NF-kappa B-dependent manner. Cu+ but not Cu2+ stimulated TNF-alpha protein release and promoter activity but with less potency. Fe2+ caused a disappearance of the cytosolic inhibitor kappa Balpha , 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-kappa B but coinciding with activation of inhibitor kappa B kinase (IKK) but not c-Jun NH2-terminal kinase. In conclusion, Fe2+ serves as a direct agonist to activate IKK, NF-kappa B, and TNF-alpha promoter activity and to induce the release of TNF-alpha 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-alpha -dependent liver injury.

tumor necrosis factor-alpha ; free radical; promoter; inhibitor kappa B kinase; electron paramagnetic resonance; nuclear factor-kappa B


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