Nucleotide Oligomerization Domain 1 Enhances IFN-γ Signaling in Gastric Epithelial Cells during Helicobacter pylori Infection and Exacerbates Disease Severity

Abstract

Virulent Helicobacter pylori strains that specifically activate signaling in epithelial cells via the innate immune molecule, nucleotide oligomerization domain 1 (NOD1), are more frequently associated with IFN-γ–dependent inflammation and with severe clinical outcomes (i.e., gastric cancer and peptic ulceration). In cell culture models, we showed that H. pylori activation of the NOD1 pathway caused enhanced proinflammatory signaling in epithelial cells in response to IFN-γ stimulation through the direct effects of H. pylori on two components of the IFN-γ signaling pathway, STAT1 and IFN regulatory factor 1 (IRF1). Specifically, H. pylori activation of the NOD1 pathway was shown to increase the levels of STAT1-Tyr701/Ser727 phosphorylation and IRF1 expression/synthesis in cells, resulting in enhanced production of the NOD1- and IFN-γ–regulated chemokines, IL-8– and IFN-γ–induced protein 10, respectively. Consistent with the notion that heightened proinflammatory signaling in epithelial cells may have an impact on disease severity, we observed significantly increased expression levels of NOD1, CXCL8, IRF1, and CXCL10 in human gastric biopsies displaying severe gastritis, when compared with those without gastritis (p < 0.05, p < 0.001, p < 0.01, and p < 0.05, respectively). Interestingly, NOD1, CXCL8, and IRF1 expression levels were also significantly upregulated in gastric tumor tissues, when compared with paired nontumor samples (p < 0.0001, p < 0.05, and p < 0.05, respectively). Thus, we propose that cross-talk between NOD1 and IFN-γ signaling pathways contribute to H. pylori–induced inflammatory responses, potentially revealing a novel mechanism whereby virulent H. pylori strains promote more severe disease.

Helicobacter pylori Infection Activates Src Homology-2 Domain–Containing Phosphatase 2 To Suppress IFN-γ Signaling

“…The different strains of H. pylori may cause the different responses to IFN-g. We suggest that CagA-mediated IFN-g resistance occurs only within CagA-positive cells because CagA mediates SHP2 activation (8). Inconsistent with the previous study that H. pylori infection primes epithelial cells to facilitate IFN-g-induced inflammation (53), the different conclusions from these studies may result from the differing MOI used in these studies. We showed that, at a higher MOI (MOI of 100), cells are resistant to IFN-g signaling.…”

“…We showed that, at a higher MOI (MOI of 100), cells are resistant to IFN-g signaling. However, at a lower MOI (MOI of 10), the pathogen-cell contact and/or the soluble mediators secreted from infected cells may prime the activation of IFN-g in CagA-negative cells (53). Our preliminary data showed there was no inhibition on IFN-g-activated STAT1 in H. pylori-infected MKN45 cells under the lower MOI (data not shown).…”

Modification of Helicobacter pylori Peptidoglycan Enhances NOD1 Activation and Promotes Cancer of the Stomach

“…We also found in a Colombian population of patients with intestinal-type gastric cancer, that levels of NOD1 were significantly lower in cancer versus non-cancer specimens, and this was accompanied by an increase in expression of the intestinal-specific transcription factor CDX2 . This is of interest as Allison and colleagues found differing results (37). Specifically, their results from patients residing in Australia indicated that mRNA expression levels of NOD1 were increased in cancer versus non-tumor samples (37).…”

Helicobacter pylori and Gastric Cancer

“…H. pylori -induced activation of NOD1 can lead to higher expression of IL8- and IFNγ-related signaling [180]. An increased gene expression of IL8 , IL10 and TNFα that is induced by H. pylori -dependent TLR activation has been shown in adult patients with gastritis or further advanced diseases stages but also already in children positive for the infection [181,182,183].…”