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-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.

Uptake of apoptotic DC converts immature DC into tolerogenic DC that induce differentiation of Foxp3+ Treg

“…TaqMan real-time RT-PCR was carried out as described previously using primer sequences listed in Table 1 [36].…”

Multiple roles of the epithelium-specific ETS transcription factor, ESE-1, in development and disease

“…44 Furthermore, this cytokine-induced expression of ESE-1 is mediated by activation of the transcription factor, nuclear factor-kB (NF-kB), and after thorough characterization of the ESE-1 gene promoter, the NF-kB binding sequences that are required for this upregulation of ESE-1 expression were identified. 44 Indeed, others have also previously shown the presence of TATA and CCAAT boxes, as well as potential binding sites for various ETS factors and NF-kB within the promoter region of the ESE-1 gene. 45 In addition, we had also demonstrated that ESE-1 upregulates the expression of another member of the ESE subfamily of ETS transcription factors, ESE-3, and downregulates its own induction by cytokines, IL-1b and TNF-a.…”

“…34 In human colonic epithelial cells, ESE-1 has also been shown to regulate gene expression of the proinflammatory cytokine, macrophage inflammatory protein-3a (MIP-3a). 39 Another group has previously reported that CR6-interacting factor 1 (Crif1) plays an essential role in Elf3-mediated intestinal development by functioning as a transcriptional co-activator of Elf3 during terminal differentiation of the 25,30 Mouse bronchiolar airway epithelium 42 Mouse embryonal carcinoma cell line (F9) 33,35,37 Human embryonic kidney cell line (HEK 293T) 33,35,37 Human hepatoblastoma cell line (HepG2) 31 Human gastric cancer cell line (SNU-620) 31 Human colon cancer cell line (RKO) 34 Human breast cancer cell lines (SK-BR3, Hs578t) 31,32 Human cervical cancer cell line (HeLa 229) 31,33 Macrophage inflammatory protein-3a (MIP-3a)m Human colonic epithelial cell line (Caco-2) 39 Small proline-rich protein 1B (SPRR1B)m Primary human tracheobronchial epithelial cells 41 Human bronchial epithelial cell line (BEAS-2B) 41 Human lung adenocarcinoma epithelial cell line (NCI-H441) 41 Epithelium-specific ETS transcription factor-3 (ESE-3)m Human bronchial epithelial cell line (BEAS-2B) 44 Human lung carcinoma cell line (A549) 44 Interleukin-6 (IL-6)m Mouse lung tissue 44 Primary mouse airway epithelial cells 47 Primary mouse bone marrow-derived dendritic cells 47 Human bronchial epithelial cell line (BEAS-2B) 47 Interleukin-12 (IL-12)m Primary mouse bone marrow-derived dendritic cells 47 Lysozyme (LYZ)m Primary human bronchial airway epithelial cells 46 Human lung carcinoma cell line (A549) 46 Human lung mucoepidermoid carcinoma-derived cell line (NCI-H292) 46 Human lung adenocarcinoma epithelial cell line (NCI-H441) …”

Elf3 plays a role in regulating bronchiolar epithelial repair kinetics following Clara cell-specific injury

“…30 This phenotypic rescue provides further in vivo evidence that Elf3 is the critical upstream regulator of TGF-b RII expression in the mouse small intestinal epithelium. 30 In addition, we have previously shown reduced expression of the proinflammatory cytokine, interleukin-6 (IL-6), in the lungs of Elf3À/À mice when compared with their wild-type littermates after intranasal instillation of lipopolysaccharide, 31 suggesting a possible role for Elf3 in the regulation of IL-6 expression. Both TGF-b RII (see Zhao et al 32 ) and IL-6 (see Kida et al 33 ) have also been shown to be involved in the process of lung injury and repair.…”