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1 Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
2 Center for Environmental Medicine, Asthma, and Lung Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
3 Center for Environmental Medicine, Asthma, and Lung Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
4 Human Studies Division, National Health and Environmental Effects Research Laboratory, Chapel Hill, NC, USA
* To whom correspondence should be addressed. E-mail: Samet.James{at}epa.gov.
Exposure to zinc-laden particulate matter (PM) in ambient and occupational settings has been associated with proinflammatory responses in the lung. IL-8 is an important proinflammatory cytokine in the human lung and is induced in human airway epithelial cells exposed to zinc. In this study, we examined the cellular mechanisms responsible for Zn2+-induced IL-8 expression. Zn2+ stimulation resulted in pronounced increases in both IL-8 mRNA and protein expression in the human airway epithelial cell line (BEAS 2B). IL-8 promoter activity was significantly increased by Zn2+ exposure in BEAS 2B cells, indicating that Zn2+-induced IL-8 expression is transcriptionally mediated. Mutation of the AP-1 response element in an IL-8 promoter EGFP construct reduced Zn2+-induced IL-8 promoter activity. Moreover, Zn2+ exposure of BEAS 2B cells induced the phosphorylation of the AP-1 proteins c-Fos and c-Jun. We observed that Zn2+ exposure induced the phosphorylation of the ERK, JNK and p38 MAPKs, while inhibition of ERK or JNK activity blocked IL-8 mRNA and protein expression in BEAS 2B cells treated with Zn2+. In addition, we investigated the role of protein tyrosine phosphatases in the activation of signaling by Zn2+. Zn2+ treatment inhibited ERK- and JNK-directed phosphatase activities in BEAS 2B cells. These results suggested that Zn2+-induced inhibition of phosphatase activity is an initiating event in MAPK and AP-1 activation which lead to enhanced IL-8 expression by human airway epithelial cells.
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