Regulation of epithelium-specific Ets-like factors ESE-1 and ESE-3 in airway epithelial cells： potential roles in airway inflammation

• Published in: Cell research Vol. 18; no. 6; pp. 649 - 663
• Main Authors: Wu, Jing, Duan, Rongqi, Cao, Huibi, Field, Deborah, Newnham, Catherine M, Koehler, David R, Zamel, Noe, Pritchard, Melanie A, Hertzog, Paul, Post, Martin, Tanswell, A Keith, Hu, Jim
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2008; Nature Publishing Group
• Subjects: Animals; Asthma; Base Sequence; Biomedical and Life Sciences; Cell Biology; Cell Line; Cytokines - pharmacology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Down-Regulation - drug effects; Epithelial Cells - metabolism; Epithelium - drug effects; Epithelium - metabolism; Humans; Inflammation - genetics; Inflammation Mediators - pharmacology; Life Sciences; Lipopolysaccharides - pharmacology; Mice; Mice, Knockout; Molecular Sequence Data; NF-kappa B - metabolism; Organ Specificity - drug effects; original-article; Promoter Regions, Genetic - genetics; Protein Binding - drug effects; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-ets; Respiratory System - drug effects; Respiratory System - metabolism; Respiratory System - pathology; Sequence Deletion; Transcription Factors - genetics; Transcription Factors - metabolism; Up-Regulation - drug effects; Up-Regulation - genetics; 上皮细胞; 基因调节; 转录因子; transcription factor; airway disease; epithelium; asthma; gene regulation
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/cr.2008.57

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-1β （IL-1β） and tumor necrosis factor-α （TNF-α） in bronchial epithelial cell lines. Treatment of these cells with IL-1β and TNF-α 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-κB. We have characterized the ESE-1 and ESE-3 promoters and have identified the NF-κB 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 E/f3 （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.