ORIGINAL ARTICLE Cell Research (2008): 649-663 Regulation of epithelium-specific Ets-like factors ESE-1 and ESE-3 in airway epithelial cells: potential roles in airway inflammationJing Wu1, Rongqi Duan1, Huibi Cao1, Deborah Field1, Catherine M Newnham1, David R Koehler1,2, Noe Zamel3, Melanie A Pritchard4, Paul Hertzog4, Martin Post1,2,5,6, A Keith Tanswell1,5,6 and Jim Hu1,2,5 1Department 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, Canada2Department of Laboratory Medicine and Pathobiology, The University of Toronto, Toronto, Ontario M5G 1X8, Canada 3Department of Medicine, The University of Toronto, Toronto, Ontario M5G 1X8, Canada 4Center for Functional Genomics and Human Disease, Monash Institute of Medical Research, Monash University, Victoria, Australia 5Department of Paediatrics, The University of Toronto, Toronto, Ontario M5G 1X8, Canada 6Department of Physiology, The University of Toronto, Toronto, Ontario M5G 1X8, Canada
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 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. Cell Research (2008) 18:649-663. doi: 10.1038/cr.2008.57; published online 13 May 2008 Keywords: epithelium, transcription factor, airway disease, asthma, gene regulation |
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