title: Toll-like receptor 4 activation in Barrett's esophagus results in a strong increase in COX-2 expression.
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.
  
  
  CONCLUSIONS
  TLR4 activation in BE results in a strong increase in COX-2 and may contribute to malignant transformation.
authors: Department of Gastroenterology and Hepatology (F02.618), University Medical Center Utrecht, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands, r.e.verbeek-2@umcutrecht.nl.
authors: Romy E
authors: RE
authors: Verbeek
authors: Peter D
authors: PD
authors: Siersema
authors: Fiebo J
authors: FJ
authors: Ten Kate
authors: Kees
authors: K
authors: Fluiter
authors: Rhonda F
authors: RF
authors: Souza
authors: Frank P
authors: FP
authors: Vleggaar
authors: Pauline
authors: P
authors: Bus
authors: Jantine W P M
authors: JW
authors: van Baal
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001471:Barrett Esophagus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001706:Biopsy; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004942:Esophagitis, Peptic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D046509:Tissue Culture Techniques; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D016209:Interleukin-8; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; C495345:TLR4 protein, human; C410602:TOLLIP protein, human; D051197:Toll-Like Receptor 4; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human
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