Interleukin-8 Regulates Expression of Reg Protein in Helicobacter pylori-Infected Gastric Mucosa

Abstract

Chronic inflammation induced by Helicobacter pylori infection is closely associated with epithelial cell proliferation and apoptosis, which are related to cellular turnover in gastric mucosa. Reg protein is a regenerating gene product and a potent growth factor for gastric mucosal cells, however, little is known regarding its association with the pathogenesis of H. pylori infection. The aim of this study was to investigate Reg protein production and its regulation in H. pylori-associated gastritis. Gastric fundic biopsy samples were taken from patients with and without H. pylori infection. In vivo expression of Reg protein was examined by Western blotting and immunohistochemistry methods. The effects of interleukin (IL)-8 on Reg protein expression and transcriptional activation of the Reg gene in ECC10 cells were investigated by Western blotting and luciferase assays, respectively. Reg expression was found localized in the deeper part of gastric fundic glands and clearly shown in chromogranin A-positive cells in the gastric corpus. Semiquantitative immunohistochemistry and Western blotting results for Reg expression were significantly associated with polymorphonuclear neutrophil activity and chronic inflammation of gastric mucosa. IL-8 production in the gastric mucosa was significantly augmented by H. pylori infection, while IL-8 dose-dependently stimulated Reg protein production and Reg promoter activity in vitro in cultured ECC10 cells. The present study showed for the first time that Reg protein may be a potent stimulator of gastric epithelial cells in H. pylori-infected human gastric mucosa stimulated by IL-8. Further, our findings provide evidence of a novel link between Reg protein and H. pylori infection, which may help explain the molecular mechanisms underlying H. pylori-associated diseases, including gastric cancer.