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Enhanced Expression of Interleukin-8 and Activation of Nuclear Factor Kappa-B in Endoscopy-negative Gastroesophageal Reflux Disease

OBJECTIVE:Interleukin-8 (IL-8) mediates neutrophil trafficking via its receptors. Recent studies have shown that IL-8 is likely involved in the development and progression of erosive reflux esophagitis (RE), yet little is known about its implication in endoscopy-negative gastroesophageal reflux disease (GERD). The purpose of this study was to determine IL-8 messenger ribonucleic acid (mRNA) expression levels in endoscopy-negative GERD, along with assessment of nuclear factor kappaB (NF-κB) activation, which upregulates IL-8 expression.METHODS:We studied 31 patients with endoscopy-negative GERD, 15 patients with erosive RE, and 15 asymptomatic controls. Paired biopsy samples were taken from the esophagus 3 cm above the gastroesophageal junction; one biopsy was snap-frozen for measurement of IL-8 mRNA levels by real-time quantitative polymerase chain reaction, and another was formalin-fixed for histopathological evaluation. In nine endoscopy-negative GERD patients, the IL-8 mRNA expression levels were measured before and 8 wk after treatment with lansoprazole. We also sampled additional specimens for NF-κB-DNA binding assay and immunohistochemical analyses of NF-κB p65 and p50 subunits, IL-8 and specific IL-8 receptor, CXCR-1.RESULTS:The relative IL-8 mRNA expression levels were significantly higher in esophageal mucosa of patients with endoscopy-negative GERD than those of the controls. The presence of basal zone hyperplasia and intraepithelial neutrophils, histopathological hallmarks of GERD, were associated with higher levels of IL-8 mRNA. Lansoprazole treatment significantly reduced the IL-8 mRNA expression levels. The esophageal epithelium of patients with GERD showed intense immunoreactivity for IL-8, and expressed CXCR-1 antigen. We found NF-κB activation in esophageal mucosa in GERD patients and the NF-κB subunits were localized predominantly in the nuclei of IL-8-expressing cells.CONCLUSIONS:Our results demonstrate enhanced mucosal expression of IL-8 in incipient GERD even without mucosal breaks. NF-κB activation may be implicated in the pathogenesis in GERD.