Nucleotide oligomerization domain 1 enhances IFN-γ signaling in gastric epithelial cells during Helicobacter pylori infection and exacerbates disease severity.
J Immunol
; 190(7): 3706-15, 2013 Apr 01.
Article
em En
| MEDLINE
| ID: mdl-23460743
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Infecções por Helicobacter
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Interferon gama
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Células Epiteliais
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Proteína Adaptadora de Sinalização NOD1
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Mucosa Gástrica
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article