<i>Helicobacter pylori</i>Induces MAPK Phosphorylation and AP-1 Activation via a NOD1-Dependent Mechanism

Allison, Cody; Kufer, Thomas A.; Kremmer, Elisabeth; Kaparakis, Maria; Ferrero, Richard L.

doi:10.4049/jimmunol.0900664

Cited by 157 publications

(181 citation statements)

References 90 publications

(68 reference statements)

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“…Secretion of the potent chemoattractants, IL-8 and IP-10, were measured to assess NF-kB and IFN-g proinflammatory signaling, respectively, and as a means of investigating the ability of epithelial cells to recruit and direct adaptive immune responses. Consistent with previous data (1,34,40), AGS cells treated with siRNA to NOD1 secreted significantly less IL-8 than AGS control cells treated with scrambled siRNA (Fig. 1A), in response to stimulation with wild-type (WT) H. pylori bacteria.…”

Section: Resultssupporting

confidence: 92%

“…Although H. pylori CagA has been reported to mediate IL-8 responses in AGS gastric epithelial cells (44), we observed no differences between the IL-8 responses induced in MKN28 cells by WT bacteria, when compared with isogenic DcagA organisms. This result is consistent with previous findings from our group for AGS cells (1,40) and may be attributed to the relatively short bacteria-cell contact time used in our studies (i.e., 1 h). Costimulation of cells with H. pylori and IFN-g induced robust IL-8, IP-10, and MIG responses in MKN28 cells ( Fig.…”

Section: Ifn-g-inducible Chemokine Responses In Epithelial Cells Are supporting

confidence: 94%

“…pylori strains 251 (36) and G27 (37) and isogenic 251 ΔcagPAI (38), G27 ΔcagA, and G27 ΔcagM (this study) mutants were constructed by natural transformation as described previously (39). Bacteria were cultured in microaerobic conditions on blood agar medium (40). For stimulations, washed H. pylori broth cultures were added to antibiotic-free serumstarved cells at a 1:10 multiplicity of infection (40).…”

Section: Bacteria and Stimulationsmentioning

confidence: 99%

“…Bacteria were cultured in microaerobic conditions on blood agar medium (40). For stimulations, washed H. pylori broth cultures were added to antibiotic-free serumstarved cells at a 1:10 multiplicity of infection (40). For IFN-g cotreatment assays, bacteria were removed after 1 h, and cells were treated with 20 ng/ml IFN-g (Millipore, Billerica, MA) after 4 h.…”

Section: Bacteria and Stimulationsmentioning

confidence: 99%

“…Proteins were transferred to nitrocellulose membrane using the iBlot System (Life Technologies), as described previously (40). Membranes were incubated with either anti-phospho-STAT1 (Tyr 701 ), anti-phospho-STAT1 (Ser 727 ), total anti-STAT1 (Santa Cruz Biotechnology), anti-IRF1 (Cell Signaling Technology, Arundel, QLD, Australia) (all at 1:1000), or anti-actin (1:3,000) Abs, respectively, followed by a goatanti-rabbit HRP-conjugated IgG (1:1,000-10,000) secondary Ab (Millipore).…”

Section: Immunoblottingmentioning

confidence: 99%

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

Allison

Ferrand

McLeod

et al. 2013

The Journal of Immunology

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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.

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Section: Resultssupporting

confidence: 92%

Section: Ifn-g-inducible Chemokine Responses In Epithelial Cells Are supporting

confidence: 94%

Section: Bacteria and Stimulationsmentioning

confidence: 99%

Section: Bacteria and Stimulationsmentioning

confidence: 99%

Section: Immunoblottingmentioning

confidence: 99%

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

Allison

Ferrand

McLeod

et al. 2013

The Journal of Immunology

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Bidirectional regulation between TMEFF2 and STAT3 may contribute to Helicobacter pylori‐associated gastric carcinogenesis

Sun

Tang

et al. 2014

Intl Journal of Cancer

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The transmembrane protein with epidermal growth factor and two follistatin motifs 2 (TMEFF2) is a single-pass transmembrane protein, and it is downregulated in human gastric cancer and levels correlate with tumor progression and time of survival. However, the mechanism of its dysregulation in gastric cancer is little known. Here we investigate its regulatory mechanism and the bidirectional regulation between TMEFF2 and STAT3 in gastric carcinogenesis. TMEFF2 expression was decreased after Helicobacter pylori (H. pylori) infection in vivo and in vitro. STAT3 directly binds to the promoter of TMEFF2 and regulates H. pylori-induced TMEFF2 downregulation in normal gastric GES-1 cells and gastric cancer AGS cells. Conversely, TMEFF2 may suppress the phosphorylation of STAT3 and TMEFF2-induced downregulation of STAT3 phosphorylation may depend on SHP-1. A highly inverse correlation between the expression of TMEFF2 and pSTAT3 was also revealed in gastric tissues. We now show the deregulation mechanism of TMEFF2 in gastric carcinogenesis and identify TMEFF2 as a new target gene of STAT3. The phosphorylation of STAT3 may be negatively regulated by TMEFF2, and the bidirectional regulation between TMEFF2 and STAT3 may contribute to H. pylori-associated gastric carcinogenesis.V C 2014 UICC Gastric cancer (GC) is the second leading cause of cancerrelated death worldwide.1 Most patients are diagnosed at an advantaged stage because of lack of early specific symptoms and eventually dead after operation because of recurrence and metastasis. 2,3Helicobacter pylori (H. pylori) is considered as the strongest risk factor among the host genetic and environmental factors influencing the occurrence and progression of GCs. 4,5 H. pylori triggers multiple pathways (JAK/STAT3, NF-jB, PI3K/Akt, Wnt/b-catenin and Ras/Erk) in gastric epithelial

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ICOS⁺Foxp3⁺TILs in gastric cancer are prognostic markers and effector regulatory T cells associated withHelicobacter pylori

et al. 2016

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Regulatory T cells (Tregs) have an immunosuppressive role in the tumor microenvironment. Since effector Tregs (eTregs), which have highly suppressive functions, are located in a subpopulation of Foxp3 CD4 Tregs, the TCR-inducible costimulatory receptor (ICOS) was applied as a marker of eTregs that infiltrated gastric cancer tissue and the induction pathway of ICOS Foxp3 cells was analyzed by flow cytometry and immunohistochemistry. In tumor-infiltrating lymphocytes (TILs), ICOS Foxp3 CD4 T cells were abundantly observed in the late stages of gastric cancer. ICOS CD4 TILs exhibited the ability to produce IL-10, but not IFN-γ, TNF, or IL-17 and also to suppress the proliferation of CFSE-labeled responder CD8 T cells. With the agonistic ICOS-L protein (rICOS-L Ig), ICOS Foxp3 cells were efficiently induced from naive CD4 T cells under a stimulation with TGF-β and CD3/CD28 mAbs. Furthermore, when A*0201 PBMCs were cultured with the CMV or Melan-A antigenic peptide and rICOS-L Ig, the induction of CMV or Melan-A tetramer-binding CD8 T cells, respectively, was inhibited. The expression of ICOS in Foxp3 cells was closely related to plasmacytoid dendritic cells (pDCs) and their expression of ICOS-L and TLR9 as well as Helicobacter pylori infection. Collectively, our results demonstrate the potential of ICOS as a promising target for direct Treg-targeting therapeutic agents for gastric cancer, and that of eradicating therapy for H. pylori as an indirect immune therapy for gastric cancer.

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Helicobacter pyloriInduces MAPK Phosphorylation and AP-1 Activation via a NOD1-Dependent Mechanism

Abstract: Material

Cited by 157 publications

References 90 publications

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

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

Bidirectional regulation between TMEFF2 and STAT3 may contribute to Helicobacter pylori‐associated gastric carcinogenesis

ICOS⁺Foxp3⁺TILs in gastric cancer are prognostic markers and effector regulatory T cells associated withHelicobacter pylori

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Helicobacter pyloriInduces MAPK Phosphorylation and AP-1 Activation via a NOD1-Dependent Mechanism

Abstract: Material

Cited by 157 publications

References 90 publications

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

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

Bidirectional regulation between TMEFF2 and STAT3 may contribute to Helicobacter pylori‐associated gastric carcinogenesis

ICOS+Foxp3+TILs in gastric cancer are prognostic markers and effector regulatory T cells associated withHelicobacter pylori

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ICOS⁺Foxp3⁺TILs in gastric cancer are prognostic markers and effector regulatory T cells associated withHelicobacter pylori