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Response to TNF-α Is Increasing Along with the Progression in Barrett’s Esophagus

Abstract

Background and Aims

Barrett’s esophagus, a metaplasia resulting from a long-standing reflux disease, and its progression to esophageal adenocarcinoma (EAC) are characterized by activation of pro-inflammatory pathways, induced by cytokines.

Methods

An in vitro cell culture system representing the sequence of squamous epithelium (EPC1 and EPC2), Barrett’s metaplasia (CP-A), dysplasia (CP-B) to EAC (OE33 and OE19) was used to investigate TNF-α-mediated induction of interleukin-8 (IL-8).

Results

IL-6 and IL-8 expressions are increasing with the progression of Barrett’s esophagus, with the highest expression of both cytokines in the dysplastic cell line CP-B. IL-8 expression in EAC cells was approx. 4.4-fold (OE33) and eightfold (OE19) higher in EAC cells than in squamous epithelium cells (EPC1 and EPC2). The pro-inflammatory cytokine TNF-α increased IL-8 expression in a time-, concentration-, and stage-specific manner. Furthermore, TNF-α changed the EMT marker profile in OE33 cells by decreasing the epithelial marker E-cadherin and increasing the mesenchymal marker vimentin. The anti-inflammatory compound curcumin was able to repress proliferation and to activate apoptosis in both EAC cell lines.

Conclusion

The increased basal expression levels of IL-8 with the progression of Barrett’s esophagus constrain NFκB activation and its contribution in the manifestation of Barrett’s esophagus. An anti-inflammatory compound, such as curcumin, could create an anti-inflammatory microenvironment and thus potentially support an increase chemosensitivity in EAC cells.

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Acknowledgments

The authors would like to thank Franziska Rolfs and Ulrike Schmiedek for excellent technical support. This work was supported by the Junior Research Grant of the Faculty of Medicine, University of Leipzig, to RT and OL.

Funding

This work was supported by the Junior Research Grant of the Faculty of Medicine, University of Leipzig to RT.

Author’s contribution

OC, KG, RT, and IG conceived and designed experiments. OC, KG, LM, OL, and RT developed methodology. OC, KG, LM, IG, and RT analyzed and interpreted the data. AD, UE, OL, BJW, and AH were provided administrative, technical or material support. OC, RT, and IG wrote and/or revised the manuscript. RT and IG supervised and coordinated all aspects of the work.

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Correspondence to René Thieme.

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Chemnitzer, O., Götzel, K., Maurer, L. et al. Response to TNF-α Is Increasing Along with the Progression in Barrett’s Esophagus. Dig Dis Sci 62, 3391–3401 (2017). https://doi.org/10.1007/s10620-017-4821-6

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Keywords

  • Barrett’s esophagus
  • Esophageal adenocarcinoma
  • TNF-α
  • EMT
  • Inflammation