Cadmium-mediated toxicity of lung epithelia is enhanced through NF-κB-mediated transcriptional activation of the human zinc transporter ZIP8

TitleCadmium-mediated toxicity of lung epithelia is enhanced through NF-κB-mediated transcriptional activation of the human zinc transporter ZIP8
Publication TypeJournal Article
Year of Publication2012
AuthorsNapolitano JR, Liu M-J, Bao S, Crawford M, Nana-Sinkam P, Cormet-Boyaka E, Knoell DL
JournalAm J Physiol Lung Cell Mol Physiol
Volume302
Issue9
PaginationL909-18
Date Published2012 May 1
ISSN1522-1504
KeywordsApoptosis, Cadmium, Cation Transport Proteins, Cell Line, Cell Polarity, Cytoprotection, Epithelial Cells, Humans, Lung, Necrosis, NF-kappa B, Nitriles, Primary Cell Culture, Pulmonary Disease, Chronic Obstructive, Smoking, Sulfones, Transcriptional Activation, Tumor Necrosis Factor-alpha, Up-Regulation, Zinc
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.

DOI10.1152/ajplung.00351.2011
Alternate JournalAm. J. Physiol. Lung Cell Mol. Physiol.
PubMed ID22345571
PubMed Central IDPMC3362162
Grant ListR01 HLD086981-01 / / PHS HHS / United States
UL1 TR000090 / TR / NCATS NIH HHS / United States