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Am J Physiol Lung Cell Mol Physiol. 2006 May;290(5):L1028-35. Epub 2005 Dec 22.

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

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  • 1Department of Environmental Sciences and Engineering, US Environmental Protection Agency, Human Studies Facility, 104 Mason Farm Road, Chapel Hill, NC 27514, USA.

Abstract

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 Zn(2+)-induced IL-8 expression. Zn(2+) 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 Zn(2+) exposure in BEAS-2B cells, indicating that Zn(2+)-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 Zn(2+)-induced IL-8 promoter activity. Moreover, Zn(2+) exposure of BEAS-2B cells induced the phosphorylation of the AP-1 proteins c-Fos and c-Jun. We observed that Zn(2+) 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 Zn(2+). In addition, we investigated the role of protein tyrosine phosphatases in the activation of signaling by Zn(2+). Zn(2+) treatment inhibited ERK- and JNK-directed phosphatase activities in BEAS-2B cells. These results suggested that Zn(2+)-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.

PMID:
16373669
[PubMed - indexed for MEDLINE]
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