title: 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-Tyr(701)/Ser(727) 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.
authors: Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, Clayton, Victoria 3168, Australia.
authors: Cody C
authors: CC
authors: Allison
authors: Jonathan
authors: J
authors: Ferrand
authors: Louise
authors: L
authors: McLeod
authors: Mohammad
authors: M
authors: Hassan
authors: Maria
authors: M
authors: Kaparakis-Liaskos
authors: Alexandra
authors: A
authors: Grubman
authors: Prithi S
authors: PS
authors: Bhathal
authors: Anouk
authors: A
authors: Dev
authors: William
authors: W
authors: Sievert
authors: Brendan J
authors: BJ
authors: Jenkins
authors: Richard L
authors: RL
authors: Ferrero
mesh_terms: D000942:Antigens, Bacterial / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism; D002460:Cell Line; D018925:Chemokines / Q000096:biosynthesis; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism* / Q000382:microbiology; D005753:Gastric Mucosa / Q000378:metabolism* / Q000382:microbiology; D016481:Helicobacter Infections / Q000378:metabolism* / Q000382:microbiology; D016480:Helicobacter pylori / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D050856:Interferon Regulatory Factor-1 / Q000235:genetics; D007371:Interferon-gamma / Q000378:metabolism*; D053474:Nod1 Signaling Adaptor Protein / Q000378:metabolism*; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D018925:Chemokines; D050856:Interferon Regulatory Factor-1; D053474:Nod1 Signaling Adaptor Protein; D050794:STAT1 Transcription Factor; C080866:cagA protein, Helicobacter pylori; D007371:Interferon-gamma