Regulation of cyclooxygenase-2 expression by cAMP response element and mRNA stability in a human airway epithelial cell line exposed to zinc.
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+.
Center for Environmental Medicine, Asthma and Lung Biology, University of North Carolina, Chapel Hill, NC 2759, USA. Weidong_Wu@med.unc.edu
Weidong
W
Wu
Robert A
RA
Silbajoris
Dongsun
D
Cao
Philip A
PA
Bromberg
Qiao
Q
Zhang
David B
DB
Peden
James M
JM
Samet
D001665:Binding Sites; D001980:Bronchi / Q000166:cytology / Q000187:drug effects; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D020871:RNA Stability / Q000187:drug effects*; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015032:Zinc / Q000633:toxicity*
D017362:Cyclic AMP Response Element-Binding Protein; D016328:NF-kappa B; D012333:RNA, Messenger; D051546:Cyclooxygenase 2; D015032:Zinc