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

Romy E. Verbeek, Peter D. Siersema, Fiebo J. Ten Kate, Kees Fluiter, Rhonda F. Souza, Frank P. Vleggaar, Pauline Bus, Jantine W P M Van Baal

Research output: Contribution to journalReview articlepeer-review

20 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1121-1134
Number of pages14
JournalJournal of Gastroenterology
Volume49
Issue number7
DOIs
StatePublished - Jul 2014

Keywords

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

ASJC Scopus subject areas

  • Gastroenterology

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