Down-regulation of epithelial IL-8 responses inHelicobacter pylori-infected duodenal ulcer patients depends on host factors, rather than bacterial factors

Abstract

SummaryHelicobacter pylori infection is one of the most common gastrointestinal infections worldwide. Although the majority of the infected individuals remain asymptomatic carriers of the bacteria, approximately 15% develop peptic ulcers, which are most prevalent in the duodenum. H. pylori induce a vigorous immune response which, however, fails to clear the infection. Instead, the chronic inflammation that arises in the infected gastroduodenal mucosa may be involved in the development of H. pylori-associated peptic ulcers. We have previously shown that duodenal ulcer (DU) patients have a significantly lower epithelial cytokine, e.g. IL-8, response in the duodenum than asymptomatic (AS) carriers. In this study we have further investigated the mechanisms behind this finding, i.e. whether it can be explained by bacterial factors, down-regulation of epithelial cytokine production by regulatory T cells, or an impaired ability of the duodenal epithelium in DU patients to produce cytokines. Gastric AGS, and intestinal T84 epithelial cell lines were stimulated with H. pylori strains isolated from DU patients and AS carriers, respectively. All strains were found to induce comparable cytokine and cytokine receptor expression in epithelial cells. Regulatory T cells (CD4+ + + + CD25 high ), isolated from human peripheral blood and cocultured with H. pylori stimulated AGS cells, were found to slightly suppress H. pylori -induced epithelial cytokine production. Furthermore, primary cultures of duodenal epithelial cells from DU patients were found to produce markedly lower amounts of cytokines than epithelial cells isolated from AS carriers. These results suggest that the lower epithelial cytokine responses in the duodenum of DU patients, which may be of importance for the pathogenesis of H. pylori-induced duodenal ulcers, most likely can be explained by host factors, i.e. mainly a decreased ability of the duodenal epithelium to produce cytokines, but possibly partly also down-regulation by regulatory T cells.

CagA EPIYA polymorphisms in ColombianHelicobacter pyloristrains and their influence on disease-associated cellular responses

“…Cellular inflammatory response in AGS cells was shown to be independent of the pathology from which strains were isolated, although the two strains showing the highest IL-8 expression levels were isolated from patients diagnosed with gastric cancer. These results are in agreement with previous studies showing that H. pylori strains isolated from different gastric pathologies varied in their ability to induce IL-8 expression in AGS cells, but did not associate to disease severity [19,47] . Moreover, Schneider et al [27] reported in a recent study involving cagA-positive H. pylori strains isolated from Colombian patients, that IL-8 expression induced by isolates from precancerous lesions did not differ from that induced by isolates from nonatrophic gastritis.…”

The inflammatory and immune response to Helicobacter pylori infection

“…154 Moreover, IL-8 expression by H. pylori-stimulated gastric epithelial cells has been shown to be suppressed upon co-culture with human CD4 þ CD25 hi cells, indicating that Tregs may indeed modulate human gastric inflammation. 155 In mice, IL-10 promotes H. pylori colonisation and reduces inflammation. 156 Reports conflict on whether CD25þ Tregs reduce immunopathology in H. pylori infected mice, 157,158 but there is broad agreement that Tregs do modulate antibody and T-cell responses.…”

Helicobacter pylori Infection of the Gastric Mucosa

“…Consistent with the known functions of Treg's, mutations in Foxp3 result in fatal lymphoproliferative disorder in mice and an X-linked multiorgan autoimmune disease in humans. Indeed, increased frequency of Treg's both in the circulation and in the stomach of H. pylori-infected individuals compared to uninfected individuals (Lundgren et al, 2005a;Stromberg et al, 2005;Kandulski et al, 2008;Robinson et al, 2008;Jang, 2010) has been related to increased H. pylori colonization and TGF-β production (Kandulski et al, 2008). In a unique study comparing gastric biopsies from H. pylori-infected children and adults, a higher frequency of FOXP3 + Treg's was found in the stomach of H. pylori-infected children compared to adults.…”