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.
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.


METHODS
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.
Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas, USA.
Xiaofang
X
Huo
Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas, USA.
Xi
X
Zhang
Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas, USA.
Chunhua
C
Yu
Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas, USA.
Qiuyang
Q
Zhang
Department of Pediatrics, Children's Medical Center and the University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Edaire
E
Cheng
Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas, USA.
David H
DH
Wang
Departments of Surgery, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas, USA.
Thai H
TH
Pham
Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas, USA.
Stuart J
SJ
Spechler
Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical School, Dallas, Texas, USA.
Rhonda F
RF
Souza
D001647:Bile Acids and Salts / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D004942:Esophagitis, Peptic / Q000209:etiology; D004947:Esophagus / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D009853:Omeprazole / Q000494:pharmacology*; D054328:Proton Pump Inhibitors / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018808:Transcription Factor AP-1 / Q000378:metabolism
D001647:Bile Acids and Salts; D015415:Biomarkers; D016209:Interleukin-8; D016328:NF-kappa B; D054328:Proton Pump Inhibitors; D018808:Transcription Factor AP-1; D009853:Omeprazole
CHEMOKINES; EPITHELIAL CELLS; GASTROESOPHAGEAL REFLUX DISEASE; MOLECULAR MECHANISMS; PROTON PUMP INHIBITION