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Iron activates NF-kappaB in Kupffer cells
Hongyun She1, Shigang Xiong, Min Lin
1Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033-9141, USA.
Summary
Iron (Fe2+) directly activates Kupffer cells, initiating signaling pathways that increase tumor necrosis factor-alpha (TNF-alpha) production and worsen liver injury. This redox-dependent mechanism explains iron
Area of Science:
- Hepatology
- Immunology
- Molecular Biology
Background:
- Iron overload is linked to liver injury.
- Nuclear factor-kappaB (NF-kappaB) pathways are implicated in iron-induced liver damage.
Purpose of the Study:
- To investigate if iron directly activates NF-kappaB signaling in Kupffer cells.
- To determine the role of iron in stimulating tumor necrosis factor-alpha (TNF-alpha) gene expression.
Main Methods:
- Cultured rat Kupffer cells were treated with ferrous (Fe2+) and ferric (Fe3+) iron.
- TNF-alpha release, promoter activity, and NF-kappaB activation markers were measured.
- Inhibitor kappaBalpha degradation, p65 nuclear translocation, and DNA binding were assessed.
- Reactive oxygen species (ROS) and kinase activity were analyzed.
Main Results:
- Fe2+ (but not Fe3+) significantly increased TNF-alpha release and promoter activity in a NF-kappaB-dependent manner.
- Fe2+ induced degradation of inhibitor kappaBalpha and increased nuclear p65 protein.
- Fe2+ enhanced NF-kappaB DNA binding and induced hydroxyl radical (.OH) formation.
- Fe2+ activated inhibitor kappaB kinase (IKK) but not c-Jun NH2-terminal kinase.
Conclusions:
- Fe2+ acts as a direct agonist, activating IKK, NF-kappaB, and TNF-alpha expression in Kupffer cells.
- This activation occurs in a redox status-dependent manner.
- The findings provide a molecular basis for iron's role in exacerbating TNF-alpha-mediated liver injury.