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Transcription factor NF-kappaB signals antianoikic function of trefoil factor 3 on intestinal epithelial cells
1Department of Pathology, Northwestern University, Chicago, Illinois, 60614, USA.
Abstract:
Transcription factor NF-kappaB has both pro-apoptotic and anti-apoptotic properties depending on the cell type. Its role in the intestinal epithelial cell has not been well elucidated. Trefoil factor 3 (TFF3) is an anti-apoptotic peptide secreted by intestinal goblet cells. Here we show that TFF3 activated NF-kappaB p50/p65 heterodimer within 1 h in IEC-18 cells (a nontransformed rat intestinal epithelial cell line). Moreover, we found that TFF3-treated IEC-18 cells are resistant to anoikis, an anchorage-related apoptosis in epithelium. In addition, the stable expression of a mutant form of the endogenous NF-kappaB inhibitor (IkappaBalpha(mut)) in IEC-18 cells results in a significant attenuation of anti-anoikic effect of TFF3. Taken together, these data indicate that (1) TFF3 is an endogenous gastrointestinal peptide with anti-anoikic property; (2) TFF3 activates NF-kappaB in enterocytes; and (3) TFF3-induced resistance to anoikis in intestinal epithelial cells is mediated by a distinct signaling cascade linked to NF-kappaB. Furthermore, our study implicates NF-kappaB as an important regulator in survival pathway of intestinal epithelial cells.
Insights
Trefoil factor 3 (TFF3) peptide prevents anoikis, a form of cell death, in intestinal epithelial cells by activating NF-kappaB. This highlights TFF3
Area of Science:
- Gastroenterology
- Molecular Biology
- Cell Biology
Background:
- The transcription factor NF-kappaB has dual roles in apoptosis.
- The function of NF-kappaB in intestinal epithelial cells is not fully understood.
- Trefoil factor 3 (TFF3) is an anti-apoptotic peptide produced by intestinal goblet cells.
Purpose of the Study:
- To investigate the role of TFF3 in intestinal epithelial cell survival.
- To determine if TFF3 activates NF-kappaB in enterocytes.
- To elucidate the signaling pathway through which TFF3 confers resistance to anoikis.
Main Methods:
- Treatment of IEC-18 cells with TFF3.
- Analysis of NF-kappaB p50/p65 heterodimer activation.
- Assessment of anoikis resistance in TFF3-treated cells.
- Stable expression of a mutant NF-kappaB inhibitor (IkappaBalpha(mut)) to study TFF3's mechanism.
Main Results:
- TFF3 rapidly activated the NF-kappaB p50/p65 heterodimer in IEC-18 cells.
- TFF3-treated cells exhibited resistance to anoikis.
- Inhibition of NF-kappaB signaling attenuated the anti-anoikic effect of TFF3.
- These findings suggest TFF3 activates NF-kappaB, mediating resistance to anoikis.
Conclusions:
- TFF3 is an endogenous gastrointestinal peptide that confers resistance to anoikis.
- TFF3 activates NF-kappaB signaling in intestinal epithelial cells.
- NF-kappaB is a key mediator of TFF3-induced anoikis resistance and intestinal epithelial cell survival.