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-kappaB) 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-kappaB-DNA binding assay and immunohistochemical analyses of NF-kappaB 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-kappaB activation in esophageal mucosa in GERD patients and the NF-kappaB 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-kappaB activation may be implicated in the pathogenesis in GERD.
Isomoto
Hajime
H
Second Department of Internal Medicine, Nagasaki University School of Medicine, Shunkaikai Inoue Hospital, Nagasaki, Japan.
Saenko
Vladimir A
VA
Kanazawa
Yusei
Y
Nishi
Yoshito
Y
Ohtsuru
Akira
A
Inoue
Kenichiro
K
Akazawa
Yuko
Y
Takeshima
Fuminao
F
Omagari
Katsuhisa
K
Miyazaki
Masanobu
M
Mizuta
Yohei
Y
Murata
Ikuo
I
Yamashita
Shunichi
S
Kohno
Shigeru
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004945:Esophagoscopy; D004947:Esophagus / Q000378:metabolism; D005260:Female; D005764:Gastroesophageal Reflux / Q000378:metabolism* / Q000517:prevention & control; D006801:Humans; D007150:Immunohistochemistry; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009092:Mucous Membrane / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis
D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger