title: Zn2+-induced IL-8 expression involves AP-1, JNK, and ERK activities in human airway epithelial cells.
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.
authors.affiliation: Department of Environmental Sciences and Engineering, US Environmental Protection Agency, Human Studies Facility, 104 Mason Farm Road, Chapel Hill, NC 27514, USA.
authors.forename: Yu-Mee
authors.initials: YM
authors.lastname: Kim
authors.forename: William
authors.initials: W
authors.lastname: Reed
authors.forename: Weidong
authors.initials: W
authors.lastname: Wu
authors.forename: Philip A
authors.initials: PA
authors.lastname: Bromberg
authors.forename: Lee M
authors.initials: LM
authors.lastname: Graves
authors.forename: James M
authors.initials: JM
authors.lastname: Samet
mesh_terms: D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics*; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000235:genetics*; D015032:Zinc / Q000494:pharmacology*
chemical_list: D016209:Interleukin-8; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D015032:Zinc