title: Iron-dependent activation of NF-kappaB in Kupffer cells: a priming mechanism for alcoholic liver disease.
abstract: Alcoholic liver disease is associated with hepatic iron accumulation, and iron supplementation exacerbates alcoholic liver disease, suggesting the pathogenic role of iron in alcoholic liver disease. We have tested a hypothesis that iron plays a signaling role in activation of redox-sensitive nuclear factor-kappa B (NF-kappaB) and that increased iron content results in heightened expression of proinflammatory cytokines in Kupffer cells because of this signaling. In cultured Kupffer cells isolated from normal rats, treatment with a lipophilic iron chelator, 1,2-dimethyl-3-hydroxypyrid-4-one (L1), markedly reduced lipopolysaccharide (LPS)-induced NF-kappaB activation and expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6. Kupffer cells, isolated from rats with experimentally induced alcoholic liver disease, had significant increases in nonheme iron content, NF-kappaB binding, and mRNA expression for TNF-alpha and macrophage inflammatory protein-1. Ex vivo L1 treatment normalized all these parameters. Addition of ferrous iron to cultured normal rat Kupffer cells increased I-kappa B kinase (IKK) activity at 15 min and NF-kappaB binding at 30 min. L1 pretreatment completely abrogated both effects. Moreover, the iron treatment increased TNF-alpha release and TNF-alpha promoter activity in a NF-kappaB-dependent manner. Ferrous iron also transiently decreased cytoplasmic I-kappa B-alpha (IkappaB-alpha), with concomitant increases in nuclear p65 protein and DNA binding of p65/p50. Taken together, these results support the existence of iron-dependent signaling for activation of IKK/NF-kappaB in Kupffer cells, and this iron signaling serves as a target for a potential priming effect for the pathogenesis of experimental alcoholic liver disease.
authors.affiliation: Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Shigang
authors.initials: S
authors.lastname: Xiong
authors.forename: Hongyun
authors.initials: H
authors.lastname: She
authors.forename: Chin K
authors.initials: CK
authors.lastname: Sung
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tsukamoto
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D007501:Iron / Q000378:metabolism / Q000494:pharmacology*; D007728:Kupffer Cells / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008108:Liver Diseases, Alcoholic / Q000209:etiology*; D016328:NF-kappa B / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D007501:Iron