Original Article—Alimentary Tract

Journal of Gastroenterology

, Volume 49, Issue 7, pp 1121-1134

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

  • Romy E. VerbeekAffiliated withDepartment of Gastroenterology and Hepatology (F02.618), University Medical Center Utrecht Email author 
  • , Peter D. SiersemaAffiliated withDepartment of Gastroenterology and Hepatology (F02.618), University Medical Center Utrecht
  • , Fiebo J. Ten KateAffiliated withDepartment of Pathology, University Medical Center Utrecht
  • , Kees FluiterAffiliated withDepartment of Neurogenetics, Academic Medical Center, University of Amsterdam
  • , Rhonda F. SouzaAffiliated withDepartment of Medicine, University of Texas Southwestern Medical Center, VA North Texas Health Care System
  • , Frank P. VleggaarAffiliated withDepartment of Gastroenterology and Hepatology (F02.618), University Medical Center Utrecht
  • , Pauline BusAffiliated withDepartment of Gastroenterology and Hepatology (F02.618), University Medical Center Utrecht
  • , Jantine W. P. M. van BaalAffiliated withDepartment of Gastroenterology and Hepatology (F02.618), University Medical Center Utrecht

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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.

Keywords

Barrett’s esophagus Toll-like receptor 4 Cyclooxygenase-2 Esophageal adenocarcinoma