Iron activates NF- B in Kupffer cells

She, Hongyun, Shigang Xiong, Min Lin, Ebrahim Zandi, Cecilia Giulivi, and Hidekazu Tsukamoto. Iron activates NFB in Kupffer cells. Am J Physiol Gastrointest Liver Physiol 283: G719–G726, 2002; 10.1152/ajpgi.00108. 2002.— Iron exacerbates various types of liver injury in which nuclear factor (NF)B-driven genes are implicated. This study tested a hypothesis that iron directly elicits the signaling required for activation of NFB and stimulation of tumor necrosis factor (TNF)gene expression in Kupffer cells. Addition of Fe2 but not Fe3 ( 5–50 M) to cultured rat Kupffer cells increased TNFrelease and TNFpromoter activity in a NFB-dependent manner. Cu but not Cu2 stimulated TNFprotein release and promoter activity but with less potency. Fe2 caused a disappearance of the cytosolic inhibitor B , 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 NFB but coinciding with activation of inhibitor B kinase (IKK) but not c-Jun NH2-terminal kinase. In conclusion, Fe2 serves as a direct agonist to activate IKK, NFB, and TNFpromoter activity and to induce the release of TNFprotein 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-dependent liver injury.