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This Article Full Text Full Text (PDF) All Versions of this Article: 290/5/L1028    most recent 00479.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (12) Citing Articles via Google Scholar Google Scholar Articles by Kim, Y.-M. Articles by Samet, J. M. Search for Related Content PubMed PubMed Citation Articles by Kim, Y.-M. Articles by Samet, J. M.

Zn²⁺-induced IL-8 expression involves AP-1, JNK, and ERK activities in human airway epithelial cells

¹Department of Environmental Sciences and Engineering, ²Center for Environmental Medicine, Asthma, and Lung Biology, ³Department of Pharmacology, University of North Carolina, Chapel Hill; and ⁴Human Studies Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina

Submitted 10 November 2005 ; accepted in final form 20 December 2005

Exposure to zinc-laden particulate matter 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 activating protein (AP)-1 response element in an IL-8 promoter-enhanced green fluorescent protein 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 ERK, JNK, and p38 MAPKs, whereas 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 that leads to enhanced IL-8 expression by human airway epithelial cells.

interleukin-8; zinc; activating protein-1; c-Jun NH₂-terminal kinase; extracellular signal-regulated kinase; mitogen-activated protein kinase phosphatase; metal; particulate matter

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