Proinflammatory Cytokine and Nuclear Factor Kappa-B Expression along the Inflammation–Metaplasia–Dysplasia–Adenocarcinoma Sequence in the Esophagus


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Abstract

BACKGROUNDThe incidence of esophageal adenocarcinoma has increased significantly in the western world over the last 20 yr. Most cases arise in a background of chronic gastroesophageal reflux, and specialized intestinal metaplasia in Barrett's esophagus is frequently an antecedent phenotype or evident in association with adenocarcinoma. The molecular events that characterize the pathway from inflammation to metaplasia to dysplasia and adenocarcinoma are poorly understood.AIMSTo examine the expression of the proinflammatory cytokines IL-8 and IL-1β along the esophagitis, metaplasia, dysplasia, and adenocarcinoma pathway, and to correlate this with histological changes and expression of the transcription factor NF-κB.PATIENTS AND METHODSFresh biopsy specimens were collected from patients with reflux esophagitis (n= 15), Barrett's esophagus (n = 35), Barrett's adjacent to adenocarcinoma (n = 8), and esophageal adenocarcinoma (n = 35). IL-8 and IL-1β expression were measured using enzyme-linked immunosorbent assay. NF-κB expression was measured by electrophoretic mobility shift assay.RESULTSElevated expression of NF-κB was found in 2 (13%) out of 15 patients with reflux esophagitis, 21 (60%) out of 35 patients with Barrett's esophagus, and 28 (80%) out of 35 patients with esophageal adenocarcinoma. All 5 patients with Barrett's esophagus and high-grade dysplasia showed elevated expression of NF-κB. IL-8 and IL-1β were significantly increased in esophagitis, Barrett's, and adenocarcinoma compared with squamous epithelium, and in adenocarcinoma compared with all other groups. There was a stepwise increase in the expression of IL-8, IL-1β, and NF-κB from normal through Barrett's epithelium to adenocarcinoma in eight cases of esophageal adenocarcinoma. The levels of both IL-8 and IL-1β in adenocarcinoma patients correlated with stage of disease. Patients with adenocarcinoma who were NF-κB positive had significantly higher levels of both IL-8 (p = 0.04) and IL-1β (p = 0.03) compared to adenocarcinoma patients who were NF-κB negative.CONCLUSIONSThe proinflammatory cytokines IL-8 and IL-1β are elevated in esophagitis and Barrett's epithelium, and markedly elevated in adenocarcinoma. NF-κB activation is infrequent in esophagitis, but is increased in Barrett's epithelium and adenocarcinoma. The association of NF-κB activation with cytokine upregulation was only evident in patients with adenocarcinoma. These patterns may play an important role in Barrett's inflammation and tumourigenesis, and inhibition of the NF-κB/proinflammatory cytokine pathway may be an important target for future chemoprevention strategies.

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