Article Text

PDF
Original article
In oesophageal squamous cells exposed to acidic bile salt medium, omeprazole inhibits IL-8 expression through effects on nuclear factor-κB and activator protein-1
  1. Xiaofang Huo1,
  2. Xi Zhang1,
  3. Chunhua Yu1,
  4. Qiuyang Zhang1,
  5. Edaire Cheng3,
  6. David H Wang1,
  7. Thai H Pham2,
  8. Stuart J Spechler1,
  9. Rhonda F Souza1
  1. 1Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas, USA
  2. 2Departments of Surgery, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas, USA
  3. 3Department of Pediatrics, Children's Medical Center and the University of Texas Southwestern Medical Center, Dallas, Texas, USA
  1. Correspondence to Dr Stuart Jon Spechler, Division of Gastroenterology (111B1), Dallas VA Medical Center, 4500 South Lancaster Road, Dallas, TX 75216, USA; sjspechler{at}aol.com

Abstract

Objective Oesophagitis might result from the effects of chemokines produced by oesophageal cells in response to gastro-oesophageal reflux, and not solely from the direct, caustic effects of refluxed gastric juice. Proton pump inhibitors (PPI) can block chemokine production through mechanisms independent of their antisecretory effects. We studied omeprazole effects on chemokine production by oesophageal epithelial cells exposed to acidic bile salts.

Design Human primary and telomerase-immortalised oesophageal squamous cells were exposed to acidic bile salt medium with or without omeprazole pretreatment. Interleukin (IL)-8 expression was determined by RT-PCR and ELISA. IL-8 promoter activity was measured by luciferase reporter assay. Binding of NF-κB and AP-1 subunits to the IL-8 promoter was assessed by chromatin immunoprecipitation (ChIP) assay. Immune cell migration induced by conditioned medium was determined by a double-chamber migration assay system.

Results Acidic bile salt medium caused oesophageal epithelial cells to express IL-8 mRNA and protein by activating the IL-8 promoter through NF-κB and AP-1 binding. Omeprazole inhibited that acidic bile salt-stimulated IL-8 expression by blocking the nuclear translocation of p65 (an NF-κB subunit), and by blocking the binding of p65, c-jun and c-fos (AP-1 subunits) to the IL-8 promoter. Omeprazole also blocked the ability of conditioned medium from cells exposed to acidic bile salts to induce immune cell migration.

Conclusions In oesophageal squamous epithelial cells, omeprazole inhibits IL-8 expression through effects on NF-κB and AP-1 that are entirely independent of effects on gastric acid secretion. These previously unrecognised PPI effects might contribute to the healing of reflux oesophagitis.

  • GASTROESOPHAGEAL REFLUX DISEASE
  • PROTON PUMP INHIBITION
  • CHEMOKINES
  • EPITHELIAL CELLS
  • MOLECULAR MECHANISMS

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.