Journal
CELL RESEARCH
Volume 18, Issue 6, Pages 649-663Publisher
INST BIOCHEMISTRY & CELL BIOLOGY
DOI: 10.1038/cr.2008.57
Keywords
epithelium; transcription factor; airway disease; asthma; gene regulation
Categories
Funding
- CIHR [77750, 15276] Funding Source: Medline
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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-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) in bronchial epithelial cell lines. Treatment of these cells with IL-1 beta 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-kappa B. We have characterized the ESE-1 and ESE-3 promoters and have identified the NF-kappa B 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.
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