title: Cadmium-mediated toxicity of lung epithelia is enhanced through NF-κB-mediated transcriptional activation of the human zinc transporter ZIP8.
abstract: Cadmium (Cd), a toxic heavy metal and carcinogen that is abundantly present in cigarette smoke, is a cause of smoking-induced lung disease. SLC39A8 (ZIP8), a zinc transporter, is a major portal for Cd uptake into cells. We have recently identified that ZIP8 expression is under the transcriptional control of the NF-κB pathway. On the basis of this, we hypothesized that cigarette-smoke induced inflammation would increase ZIP8 expression in lung epithelia, thereby enhancing Cd uptake and cell toxicity. Herein we report that ZIP8 is a central mediator of Cd-mediated toxicity. TNF-α treatment of primary human lung epithelia and A549 cells induced ZIP8 expression, resulting in significantly higher cell death attributable to both apoptosis and necrosis following Cd exposure. Inhibition of the NF-κB pathway and ZIP8 expression significantly reduced cell toxicity. Zinc (Zn), a known cytoprotectant, prevented Cd-mediated cell toxicity via ZIP8 uptake. Consistent with cell culture findings, a significant increase in ZIP8 mRNA and protein expression was observed in the lung of chronic smokers compared with nonsmokers. From these studies, we conclude that ZIP8 expression is induced in lung epithelia in an NF-κB-dependent manner, thereby resulting in increased cell death in the presence of Cd. From this we contend that ZIP8 plays a critical role at the interface between micronutrient (Zn) metabolism and toxic metal exposure (Cd) in the lung microenvironment following cigarette smoke exposure. Furthermore, dietary Zn intake, or a lack thereof, may be a contributing factor in smoking-induced lung disease.
authors.affiliation: Integrated Biomedical Science Graduate Program, College of Medicine, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Napolitano
authors.forename: Ming-Jie
authors.initials: MJ
authors.lastname: Liu
authors.forename: Shengying
authors.initials: S
authors.lastname: Bao
authors.forename: Melissa
authors.initials: M
authors.lastname: Crawford
authors.forename: Patrick
authors.initials: P
authors.lastname: Nana-Sinkam
authors.forename: Estelle
authors.initials: E
authors.lastname: Cormet-Boyaka
authors.forename: Daren L
authors.initials: DL
authors.lastname: Knoell
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002104:Cadmium / Q000378:metabolism / Q000633:toxicity*; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D016764:Cell Polarity; D019610:Cytoprotection; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000473:pathology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009336:Necrosis / Q000139:chemically induced; D009570:Nitriles / Q000494:pharmacology; D061251:Primary Cell Culture; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism / Q000473:pathology; D012907:Smoking / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D015854:Up-Regulation; D015032:Zinc / Q000378:metabolism / Q000494:pharmacology
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D027682:Cation Transport Proteins; D016328:NF-kappa B; D009570:Nitriles; C530151:SLC39A8 protein, human; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; D002104:Cadmium; D015032:Zinc