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ZN2+ INDUCES CYTOKINE EXPRESSION IN HUMAN AIRWAY EPITHELIAL CELLS THROUGH THE ACTIVATION OF MULTIPLE SIGNALING PATHWAYS
Citation:
Samet, J M., Y. M. Kim, W. Reed, AND W. Wu. ZN2+ INDUCES CYTOKINE EXPRESSION IN HUMAN AIRWAY EPITHELIAL CELLS THROUGH THE ACTIVATION OF MULTIPLE SIGNALING PATHWAYS. Presented at American Thoracic Society Annual Meeting, San Diego, CA, March 20 - 25, 2005.
Description:
A number of studies have implicated the metallic content of ambient particulate matter (PM) with various indices of pulmonary and cardiovascular morbidity. Among the ambient PM metals, zinc is a ubiquitous contaminant known to cause adverse health effects. To assess its potential contribution to PM-induced inflammatory responses, we examined the effect of exposure to Zn2+ on cytokine expression in the human airway epithelial cell line BEAS 2B. Non-cytotoxic exposure to Zn2+ (50uM zinc sulfate up to 14 hrs) induced expression of IL-6, IL-8, and TNF-a mRNA and protein in BEAS cells. Pretreatment of BEAS with activity inhibitors of the epidermal growth factor receptor (EGFR) kinase, extracellular signal-regulated kinase (ERK) or c-Jun N-terminal kinase (JNK) (PD153035, PD98059 and SP600125, respectively), significantly reduced Zn2+-induced elevations in IL-8 mRNA and protein release. Zn2+ exposure significantly increased IL-8 promoter activity, as assessed in BEAS cells expressing a promoter-reporter construct containing IL-8 promoter elements upstream of an enhanced green fluorescence protein coding sequence. Mutation of the AP-1 response element in the IL-8 promoter significantly reduced Zn2+-induced IL-8 promoter reporter activity. In BEAS cells transduced with a 5x tandem repeat of the MHC NFkB response element upstream of a firefly luciferase coding sequence Zn2+ exposure increased NFkB dependent promoter activity more than 5 fold. These findings show that Zn2+-induces the expression of cytokines such as IL-8 through a transcriptional mechanism that is dependent on signaling pathways regulated by EGFR, ERK, and JNK activity, and involves NF-kB and AP-1 activation in BEAS cells. THIS ABSTRACT DOES NOT NECESSARILY REFLECT EPA POLICY.
Total character count : 2150 (vs.2179 ATS regulation)