Su1940 Influence of Prostate Stem Cell Antigen Gene Polymorphisms on Risk of Gastric Cancer and Duodenal Ulcer in Japanese Patients

Abstract

BACKGROUND AND AIM : IDO plays a role in self-limiting Th1 response and promoting regulatory T cells and Th2 cytokine profile, mainly represented by interleukin (IL)-4. Interleukin (IL)-17, a Th17 cells-derived cytokine up-regulated in H.pylori-infected human gastric mucosa, is involved in the host response against the bacterium and, possibly, in its clearance/ persistence. Aim of this study was to investigate the role of IDO in the host response against H.pylori. MATERIAL AND METHODS : Five antral biopsies were taken from 26 patients (13 M, median age 41 yrs, range 25-70) who underwent endoscopy for dyspeptic symptoms: 1 for urease quick test, 2 for histology (modified Sydney System score) and 2 for protein extraction. A C13-urea breath test was also performed. IDO expression was determined by Western blotting in total proteins extracted from freshly obtained gastric biopsies. In a subgroup of patients, further antral biopsies were taken, immediately placed in an organ culture chamber, and treated with and without IDO inhibitor 1-methyl-L-Trp (Sigma, St. Louis, MO). Expression of interferon (IFN)-γ mRNA and levels of T-bet, a Th1-related transcription factor, IL-17 and IL4 were determined in gastric biopsy cultures, by realtime PCR and Western blotting, respectively. The ratio of IDO, T-bet, IL-17 and IL-4 with beta-actin was calculated by densitometry. The expression of IFNγ gene was normalized to that of RPS9 housekeeping gene and showed as fold changes using the 2(-Delta Delta C(T)) (Livak) method. All values were expressed as means ± SD arbitrary units (a.u.). RESULTS : IDO expression was found enhanced in gastric biopsies from H.pylori-infected (n=11) compared to uninfected (n=15) patients (1.24±0.21 a.u. vs 0.92±0.47 a.u., P=0.033, respectively). In H.pylori-infected patients, IDO expression did not parallel gastritis score (r=-0.29, P=0.41). In gastric biopsy cultures, IDO inhibition significantly (P<0.05) increased T-bet (0.25±0.17 a.u. vs 0.51±0.26 a.u.,) and IL-17 (0.70±0.45 a.u. vs 1.00±0.58 a.u.,) while decreasing IL-4 (0.35±0.34 a.u. vs 0.24±0.23 a.u.) levels. IFN-γmRNA expression was significantly (P=0.014) higher after IDO inhibition (1±0 a.u. vs 3.1±2 a.u.). CONCLUSIONS : This study demonstrates, for the first time, that an enhanced expression of IDO takes place in H. pylori-infected human gastric mucosa. Higher IDO expression downregulates Th1 response and IL-17 levels and upregulates IL-4 production. This molecular mechanism lowers gastric inflammation, possibly contributing to the persistence of H. pylori. Targeting IDO pathway may be a new strategy for modulating H. pylori-induced mucosal immune response.