Nucleotide oligomerization domain 1 enhances IFN-gamma signaling in gastric epithelial cells during Helicobacter pylori infection and exacerbates disease severity

Cody Charles Allison, Jonathan Francois Patrice Ferrand, Louise McLeod, Mohammad Hassan, Maria Kaparakis-Liaskos, Alexandra Grubman, Prithi S Bhathal, Anouk Tara Dev, William Sievert, Brendan John Jenkins, Richard Louis Ferrero

Research output: Contribution to journalArticleResearchpeer-review

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-gamma-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-gamma stimulation through the direct effects of H. pylori on two components of the IFN-gamma 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-gamma-regulated chemokines, IL-8- and IFN-gamma-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-gamma signaling pathways contribute to H. pylori-induced inflammatory responses, potentially revealing a novel mechanism whereby virulent H. pylori strains promote more severe disease.
Original languageEnglish
Pages (from-to)3706-3715
Number of pages10
JournalJournal of Immunology
Volume190
Issue number7
DOIs
Publication statusPublished - 2013

Cite this

@article{2193da651cb54397bf698e8a541ffcb2,
title = "Nucleotide oligomerization domain 1 enhances IFN-gamma 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-gamma-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-gamma stimulation through the direct effects of H. pylori on two components of the IFN-gamma 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-gamma-regulated chemokines, IL-8- and IFN-gamma-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-gamma signaling pathways contribute to H. pylori-induced inflammatory responses, potentially revealing a novel mechanism whereby virulent H. pylori strains promote more severe disease.",
author = "Allison, {Cody Charles} and Ferrand, {Jonathan Francois Patrice} and Louise McLeod and Mohammad Hassan and Maria Kaparakis-Liaskos and Alexandra Grubman and Bhathal, {Prithi S} and Dev, {Anouk Tara} and William Sievert and Jenkins, {Brendan John} and Ferrero, {Richard Louis}",
year = "2013",
doi = "10.4049/jimmunol.1200591",
language = "English",
volume = "190",
pages = "3706--3715",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "7",

}

TY - JOUR

T1 - Nucleotide oligomerization domain 1 enhances IFN-gamma signaling in gastric epithelial cells during Helicobacter pylori infection and exacerbates disease severity

AU - Allison, Cody Charles

AU - Ferrand, Jonathan Francois Patrice

AU - McLeod, Louise

AU - Hassan, Mohammad

AU - Kaparakis-Liaskos, Maria

AU - Grubman, Alexandra

AU - Bhathal, Prithi S

AU - Dev, Anouk Tara

AU - Sievert, William

AU - Jenkins, Brendan John

AU - Ferrero, Richard Louis

PY - 2013

Y1 - 2013

N2 - 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-gamma-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-gamma stimulation through the direct effects of H. pylori on two components of the IFN-gamma 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-gamma-regulated chemokines, IL-8- and IFN-gamma-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-gamma signaling pathways contribute to H. pylori-induced inflammatory responses, potentially revealing a novel mechanism whereby virulent H. pylori strains promote more severe disease.

AB - 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-gamma-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-gamma stimulation through the direct effects of H. pylori on two components of the IFN-gamma 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-gamma-regulated chemokines, IL-8- and IFN-gamma-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-gamma signaling pathways contribute to H. pylori-induced inflammatory responses, potentially revealing a novel mechanism whereby virulent H. pylori strains promote more severe disease.

UR - http://www.ncbi.nlm.nih.gov/pubmed/23460743

U2 - 10.4049/jimmunol.1200591

DO - 10.4049/jimmunol.1200591

M3 - Article

VL - 190

SP - 3706

EP - 3715

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 7

ER -