title: Regulation of epithelium-specific Ets-like factors ESE-1 and ESE-3 in airway epithelial cells: potential roles in airway inflammation.
abstract: Airway inflammation is the hallmark of many respiratory disorders, such as asthma and cystic fibrosis. Changes in airway gene expression triggered by inflammation play a key role in the pathogenesis of these diseases. Genetic linkage studies suggest that ESE-2 and ESE-3, which encode epithelium-specific Ets-domain-containing transcription factors, are candidate asthma susceptibility genes. We report here that the expression of another member of the Ets family transcription factors ESE-1, as well as ESE-3, is upregulated by the inflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) in bronchial epithelial cell lines. Treatment of these cells with IL-1beta and TNF-alpha resulted in a dramatic increase in mRNA expression for both ESE-1 and ESE-3. We demonstrate that the induced expression is mediated by activation of the transcription factor NF-kappaB. We have characterized the ESE-1 and ESE-3 promoters and have identified the NF-kappaB binding sequences that are required for the cytokine-induced expression. In addition, we also demonstrate that ESE-1 upregulates ESE-3 expression and downregulates its own induction by cytokines. Finally, we have shown that in Elf3 (homologous to human ESE-1) knockout mice, the expression of the inflammatory cytokine interleukin-6 (IL-6) is downregulated. Our findings suggest that ESE-1 and ESE-3 play an important role in airway inflammation.
authors.affiliation: Department of Physiology and Experimental Medicine and Canadian Institutes of Health Research Group in Lung Development, The Hospital for Sick Children, The University of Toronto, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.forename: Rongqi
authors.initials: R
authors.lastname: Duan
authors.forename: Huibi
authors.initials: H
authors.lastname: Cao
authors.forename: Deborah
authors.initials: D
authors.lastname: Field
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Newnham
authors.forename: David R
authors.initials: DR
authors.lastname: Koehler
authors.forename: Noe
authors.initials: N
authors.lastname: Zamel
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Pritchard
authors.forename: Paul
authors.initials: P
authors.lastname: Hertzog
authors.forename: Martin
authors.initials: M
authors.lastname: Post
authors.forename: A Keith
authors.initials: AK
authors.lastname: Tanswell
authors.forename: Jim
authors.initials: J
authors.lastname: Hu
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D016207:Cytokines / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004847:Epithelial Cells / Q000378:metabolism*; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics; D018836:Inflammation Mediators / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D009928:Organ Specificity / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets; D012137:Respiratory System / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; C403306:EHF protein, human; C105529:ELF3 protein, human; C494436:Elf3 protein, mouse; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors