Helicobacter pylori DNA decreases pro-inflammatory cytokine production by dendritic cells and attenuates dextran sodium sulphate-induced colitis

Abstract

Background & Aims Recently there has been emerging epidemiological data to suggest Helicobacter pylori (H. pylori) may protect against certain chronic inflammatory diseases such as inflammatory bowel disease (IBD). However, the mechanism for the observed inverse association between H. pylori and IBD has not been described. Methods The frequency of immunoregulatory (IRS) to immunostimulatory (ISS) sequences within the genome of various bacteria was calculated using MacVector software. The induction of type I IFN and IL-12 responses by DNA-pulsed murine bone marrow–derived dendritic cells (BMDC) and human plasmacytoid dendritic cells (pDC) was analyzed by cytokine production. The effect of H. pylori DNA on E. coli DNA production of type I IFN and IL-12 was assessed. The in vivo significance of H. pylori DNA suppression was assessed in a DSS-model of colitis. The systemic levels of type I IFN were assessed in H. pylori-colonized and non-colonized patients. Results We showed that H. pylori DNA has a significantly elevated IRS:ISS ratio. In vitro experiments revealed the inability of H. pylori DNA to stimulate type I IFN or IL-12 production from mouse BMDCs or human pDCs. Additionally, H. pylori DNA was able to suppress E. coli-DNA production of type I IFN and IL-12. Administration of H. pylori DNA prior to the induction of DSS colitis significantly ameliorated the severity of colitis as compared to E. coli DNA or vehicle control in both an acute and chronic model. Finally, the systemic levels of type I IFN were found to be lower in H. pylori-colonized patients versus non-colonized controls. Conclusions Overall, our study indicates that H pylori DNA has the ability to down-regulate pro-inflammatory responses from DCs and this may in part explain the inverse association between H. pylori and IBD.

Helicobacter pylori: beneficial for most?

“…H. pylori DNA suppresses type 1 interferon and IL-12 production from mouse bone marrow-derived dendritic cells, possibly owing to its high immunoregulatory sequence to immunostimulatory sequence ratio. This may explain why the systemic levels of type 1 interferon were found to be lower in H. pyloricolonized patients than noncolonized controls [17]. We also showed that the administration of isolated H. pylori DNA significantly ameliorated the severity of experimental colitis in mice.…”

“…In subsequent studies we further demonstrated that H. pylori DNA decreases proinflammatory cytokine production by dendritic cells and attenuates dextran sodium sulfate-induced colitis in mice. We showed that H. pylori DNA, which has been found in the colon and stool of infected patients [15,16], has immunoregulatory properties [17]. H. pylori DNA suppresses type 1 interferon and IL-12 production from mouse bone marrow-derived dendritic cells, possibly owing to its high immunoregulatory sequence to immunostimulatory sequence ratio.…”

Helicobacter pylori γ-glutamyl transpeptidase and vacuolating cytotoxin promote gastric persistence and immune tolerance

“…Several recent studies have independently documented the distinct ability of H. pylori to reprogram DCs toward a tolerogenic phenotype in vitro and in vivo, ensuring persistence of the bacteria and cross-protecting against chronic inflammatory and autoimmune diseases (11,12,23,24). H. pylori-experienced DCs appear to preferentially prime Treg over Th1 or Th17 responses and fail to produce proinflammatory cytokines (11,12,24).…”

Helicobacter pylori DNA's anti-inflammatory effect on experimental colitis

“…In our original work, we highlighted the elevated IRS to ISS ratios across various H. pylori strains, close to 30-fold in most instances. 2 In this addendum, we aimed to determine the presence of any dominant known IRS sequence 5 in H. pylori and whether it is conserved across all H. pylori strains measured. We found that the specific IRS sequence TTTAG-GGG occurs greater than 20 times in each H. pylori genome and this sequence dominates all other known IRS sequences (Fig.…”

“…2 We turned our attention toward the HP DNA, given documentation of its presence in the stool and colon of infected patients. 3,4 Therefore, the DNA could offer a physical connection between a bacterium that strictly colonizes the stomach with an inflammatory condition that more commonly affects the small bowel and colon.…”