1. Regulation of cyclooxygenase-2 expression by cAMP response element and mRNA stability in a human airway epithelial cell line exposed to zinc.
- Author
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Wu W, Silbajoris RA, Cao D, Bromberg PA, Zhang Q, Peden DB, and Samet JM
- Subjects
- Binding Sites, Bronchi cytology, Bronchi drug effects, Cell Line, Cyclic AMP Response Element-Binding Protein metabolism, Cyclooxygenase 2 metabolism, Humans, Mutation, NF-kappa B metabolism, RNA, Messenger metabolism, Transcription, Genetic drug effects, Cyclooxygenase 2 drug effects, Gene Expression Regulation drug effects, RNA Stability drug effects, RNA, Messenger drug effects, Zinc toxicity
- Abstract
Exposure to zinc-laden particulate matter in ambient and occupational settings has been associated with proinflammatory responses in the lung. Cyclooxygenase 2-derived eicosanoids are important modulators of airway inflammation. In this study, we characterized the transcriptional and posttranscriptional events that regulate COX-2 expression in a human bronchial epithelial cell line BEAS-2B exposed to Zn2+. Zn2+ exposure resulted in pronounced increases in COX-2 mRNA and protein expression, which were prevented by pretreatment with the transcription inhibitor actinomycin D, implying the involvement of transcriptional regulation. This was supported by the observation of increased COX-2 promoter activity in Zn2+-treated BEAS-2B cells. Mutation of the cAMP response element (CRE), but not the kappaB-binding sites in the COX-2 promoter markedly reduced COX-2 promoter activity induced by Zn2+. Inhibition of NFkappaB activation did not block Zn2+-induced COX-2 expression. Measurement of mRNA stability demonstrated that Zn2+ exposure impaired the degradation of COX-2 mRNA in BEAS-2B cells. This message stabilization effect of Zn2+ exposure was shown to be dependent on the integrity of the 3'-untranslated region found in the COX-2 transcript. Taken together, these data demonstrate that the CRE and mRNA stability regulates COX-2 expression induced in BEAS-2B cells exposed to extracellular Zn2+.
- Published
- 2008
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