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Toll-like receptor 4 activation in Barrett’s esophagus results in a strong increase in COX-2 expression

  • Original Article—Alimentary Tract
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Abstract

Background

Barrett’s esophagus (BE) is known to progress to esophageal adenocarcinoma in a setting of chronic inflammation. Toll-like receptor (TLR) 4 has been linked to inflammation-associated carcinogenesis. We aimed to determine the expression and functional activity of TLR4 in the esophagus and whether TLR4 activation in BE could promote carcinogenesis by inducing COX-2 expression.

Methods

TLR4 expression in esophageal adenocarcinoma, BE, duodenum, reflux esophagitis and normal squamous esophagus biopsies was assessed using real-time PCR and validated by in situ hybridization and immunohistochemistry. Ex vivo cultures of BE, duodenum and normal squamous esophagus biopsies and a BE cell line (BAR-T) were stimulated with the TLR4 agonist lipopolysaccharide (LPS). To evaluate the effect of TLR4 activation, NF-κB activation, IL8 secretion and expression and COX-2 expression were determined.

Results

TLR4 expression was significantly increased in esophageal adenocarcinoma, BE, duodenum and reflux esophagitis compared to normal squamous esophagus. LPS stimulation resulted in NF-κB activation and a dose-dependent increase of IL8 secretion and mRNA expression. The induction of IL8 was more evident in BE compared to normal squamous esophagus. Upon LPS stimulation, COX-2 expression increased significantly in ex vivo cultured BE biopsies, which was observed in both epithelium and lamina propria cells. However, no effect was found in duodenum and normal squamous esophagus biopsies.

Conclusion

TLR4 activation in BE results in a strong increase in COX-2 and may contribute to malignant transformation.

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Abbreviations

BE:

Barrett’s esophagus

COX-2:

Cyclooxygenase-2

EAC:

Esophageal adenocarcinoma

ELISA:

Enzyme-linked immunosorbent assay

HGD:

High-grade dysplasia

IL8:

Interleukin 8

IHC:

Immunohistochemistry

ISH:

In situ hybridization

FBS:

Fetal bovin serum

IBD:

Inflammatory bowel diseases

MAPK:

Mitogen-activated protein kinases

MSK:

Mitogen- and stress-activated protein kinase

LGD:

Low-grade dysplasia

LPS:

Lipopolysaccharide

NF-κB:

Nuclear factor–κB

PBS:

Phosphate buffered saline

PGE2:

Prostaglandin E2

PPIs:

Proton pump inhibitors

Q-RT-PCR:

Quantitative reverse transcriptase polymerase chain reaction

RE:

Reflux esophagitis

SQ:

Normal squamous esophagus

TLR:

Toll-like receptor

TNFα:

Tumor necrosis factor alpha

Tollip:

Toll interacting protein

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Acknowledgments

We thank Dr. Edward E. Nieuwenhuis (General Pediatrics, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, the Netherlands) for the discussion and Dr. Folkert H.M. Morsink (Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands) for the assistance in COX-2 IHC.

Conflict of interest

PD Siersema has received unrestricted research grant support from AstraZeneca B.V., The Netherlands and Janssen B.V., The Netherlands. The other authors have nothing to disclose.

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology (F02.618), University Medical Center Utrecht, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands

    Romy E. Verbeek, Peter D. Siersema, Frank P. Vleggaar, Pauline Bus & Jantine W. P. M. van Baal

  2. Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands

    Fiebo J. Ten Kate

  3. Department of Neurogenetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    Kees Fluiter

  4. Department of Medicine, University of Texas Southwestern Medical Center, VA North Texas Health Care System, Dallas, TX, USA

    Rhonda F. Souza

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  1. Romy E. Verbeek
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Verbeek, R.E., Siersema, P.D., Ten Kate, F.J. et al. Toll-like receptor 4 activation in Barrett’s esophagus results in a strong increase in COX-2 expression. J Gastroenterol 49, 1121–1134 (2014). https://doi.org/10.1007/s00535-013-0862-6

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