Effect of genotypic differences in interleukin-1 beta on gastric acid secretion in Japanese patients infected with helicobacter pylori

Abstract

Although several studies have demonstrated a close relation between Helicobacter pylori infection and various upper gastrointestinal disorders, including gastric cancer (1–3), the specific pathophysiological explanations for this association are not known. H. pylori infection causes histological gastritis and affects gastric acid secretion (4 – 6). In patients with severe gastritis of the corpus, acid secretion is decreased markedly and the pH of gastric juice is increased (4 – 6). This decrease in acid secretion delays the elimination of bacterial toxins and products of inflammation, such as reactive oxygen radicals and nitrogen oxide (7), thereby increasing the concentration of these well-known mutagens in the stomach. Decreased acid secretion may also result in increased production of carcinogenic N-nitroso compounds because of superinfection by other bacteria or a reduction in vitamin C levels in gastric juice (8,9). An increased rate of cell turnover in inflamed mucosa further increases the opportunity for DNA damage. Moreover, decreased gastric acid secretion permits the reflux of duodenal juice, including bile, into the stomach, which can induce intestinal metaplasia, a precancerous change (10). Therefore, H. pylori–induced gastritis and subsequent acid hyposecretion may be associated with an increased risk of gastric cancer. Several inflammatory cytokines are upregulated in gastric mucosa infected with H. pylori. One of these cytokines, interleukin-1beta (IL-1 ), is important in initiating and amplifying the inflammatory responses to H. pylori infection (11). IL-1 is also a potent inhibitor of gastric acid secretion (12–14), as we have previously observed in patients infected with H. pylori (15). Increased IL-1 gene expression and severe corpus gastritis are related to increased pH of the gastric juice. In an animal model, we have recently reported that acid secretion is decreased by H. pylori infection, which is accompanied by an increase in the expression of IL-1 messenger ribonucleic acid (mRNA) in gastric mucosa as has been observed in humans. Furthermore, the decreased acid secretion in this animal model was restored to normal levels by administration of an antagonist of the IL-1 receptor (16). Therefore, IL-1 may cause the acid hyposecretion that is observed in patients with H. pylori infection and severe gastritis. Polymorphisms in the promoter region of the IL-1 gene have been associated with differences in the production of IL-1 by leukocytes in vitro (17,18). In white patients, polymorphisms in or near the interleukin gene have been associated with enhanced IL-1 production and an increased risk of gastric cancer (7). However, one of the polymorphisms (IL-1RN*2) is rare in Japan (19). Moreover, the polymorphisms in the promoter region of IL-1 (at positions 511 and 31) are closely linked and thus may not convey independent information (7,19). We studied whether gastric pH differed among the different IL-1 ( 511) genotypes in Japanese patients infected with H. pylori.