Epithelial-specific ETS-1 (ESE1/ELF3) regulates apoptosis of intestinal epithelial cells in ulcerative colitis via accelerating NF-κB activation

Abstract

Epithelial-specific ETS-1 (ESE1), also named as ELF3, ERT and ESX, belonging to the ETS family of transcription factors, exerts multiple activities in inflammation, epithelial differentiation and cancer development. Previous data demonstrated that ESE1 synergizes with NF-κB to induce inflammation and drive tumor progress, and the nuclear translocation of ESE1 promotes colon cells apoptosis. However, the expression and biological functions of ESE1 in ulcerative colitis (UC) remain unclear. In this study, we reported for the first time that ESE1/ELF3 was over-expressed in intestinal epithelial cells (IECs) of patients with UC. In DSS-induced colitis mouse models, we observed the up-regulation of ESE1/ELF3 accompanied with the elevated levels of IEC apoptotic markers (active caspase-3 and cleaved PARP) and NF-κB activation indicators [phosphorylated NF-κB p65 subunit (p-p65) and p-IκB] in colitis IECs. Increased co-localization of ESE1/ELF3 with active caspase-3 (and p-p65) in IECs of the DSS-induced colitis group further indicated the possible involvement of ESE1/ELF3 in NF-κB-mediated IEC apoptosis in UC. Employing the TNF-α-treated HT-29 cells as an IEC apoptosis model, we confirmed the positive correlation of ESE1/ELF3 with NF-κB activation and caspase-dependent IEC apoptosis in vitro. Immunoprecipitation and immunofluorescence assay revealed the physical interaction and increased nuclear translocation of ESE1/ELF3 and the NF-κB p65 subunit in TNF-α-treated HT-29 cells. Knocking ESE1/ELF3 down by siRNA significantly alleviated TNF-α-induced NF-κB activation and cellular apoptosis in HT-29 cells. Taken together, our data suggested that ESE1/ELF3 may promote the UC progression via accelerating NF-κB activation and thus facilitating IEC apoptosis.

Functional enrichments of disease variants across thousands of independent loci in eight diseases

“…ERG mediates AD-like neurodegeneration in Down's syndrome 31 ; RXRA alters brain cholesterol metabolism in AD 32 ; and STAT3 mediates amyloid--induced apoptosis, the classical hallmark of AD 33 . We identified ELF3 in CD, which is over-expressed in ulcerative colitis (UC) cases 34 , supporting prior work suggesting CD and UC share common genetic factors 35 . We identified MEF2A in CAD, which has been previously identified in linkage studies of autosomal dominant CAD 36 .…”

Down-regulation of toll-like receptor 4 alleviates intestinal ischemia reperfusion injury and acute lung injury in mice

“…This demonstrates that TLR4 knock-down is protective against IR injury in the local intestine and the distal lung organ through the NF-κB pathway. Since NF-κB is reported to be a major route for apoptosis in a variety of cell types including the intestinal epithelial cells [37] and pulmonary microvascular epithelial cells [38], we evaluated the expression of caspase-3, an “effector” protease in the apoptotic cascade, which is usually marked in intestinal IR. Consistent with our expectation, the results in our study showed that caspase-3 expression in the lung tissues was significantly decreased by TLR4 knock-down after IR.…”

ESE1 is Associated with Neuronal Apoptosis in Lipopolysaccharide Induced Neuroinflammation

“…Reports show that ESE1 not only participates in inflammation but also in cell apoptosis. ESE1 regulates apoptosis of intestinal epithelial cells in ulcerative colitis [27] and orchestrates a positive feedback loop that constitutively activates NF-κB and drives prostate cancer progression [39]. Our study showed that ESE1 could increase neuronal apoptosis and NF-κB activity in neurons in response to CM.…”

“…LPS induces the activation of pro-inflammatory cytokines, and other signaling pathways that ultimately lead to apoptosis and cell death. ESE1 also regulates apoptosis of intestinal epithelial cells in ulcerative colitis via accelerating NF-κB activation [27,28]. However, the role of ESE1 in neuron in CNS inflammation model is still unclear.…”

“…Double immunofluorescence staining of cleaved-caspase3 (red) and ESE1 (green) was performed at day 1 after LPS injection (h-j). Scale bars 50 μm (Color figure online) [27]. Furthermore, ESE1 can interact with NF-κB.…”