Helicobacter pylori inhibits dendritic cell maturation via interleukin-10-mediated activation of the signal transducer and activator of transcription 3 pathway

David Rizzuti, Michelle Ang, Christiane Sokollik, Ted Wu, Majd Abdullah, Laura Greenfield, Ramzi Fattouh, Colin Reardon, Michael Tang, Jun Diao, Christian Schindler, Mark Cattral, Nicola L. Jones

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Helicobacter pylori infects the human gastric mucosa causing a chronic infection that is the primary risk factor for gastric cancer development. Recent studies demonstrate that H. pylori promotes tolerogenic dendritic cell (DC) development indicating that this bacterium evades the host immune response. However, the signaling pathways involved in modulating DC activation during infection remain unclear. Here, we report that H. pylori infection activated the signal transducer and activator of transcription 3 (STAT3) pathway in murine bone marrow-derived DCs (BMDCs) and splenic DCs isolated ex vivo. Isogenic cagA-, cagE-, vacA- and urease-mutants exhibited levels of phosphoSTAT3 that were comparable to in the wild-type (WT) parent strain. H. pylori-infected BMDCs produced increased immunosuppressive IL-10, which activated STAT3 in an autocrine/paracrine fashion. Neutralization of IL-10 prevented H. pylori-mediated STAT3 activation in both BMDCs and splenic DCs. In addition, anti-IL-10 treatment of infected H. pylori-BMDCs was associated with increased CD86 and MHC II expression and enhanced proinflammatory IL-1β cytokine secretion. Finally, increased CD86 and MHC II expression was detected in H. pylori-infected STAT3 knockout DCs when compared to WT controls. Together, these results demonstrate that H. pylori infection induces IL-10 secretion in DCs, which activates STAT3, thereby modulating DC maturation and reducing IL-1β secretion. These findings identify a host molecular mechanism by which H. pylori can manipulate the innate immune response to potentially favor chronic infection and promote carcinogenesis.

Original languageEnglish (US)
Pages (from-to)199-211
Number of pages13
JournalJournal of Innate Immunity
Volume7
Issue number2
DOIs
StatePublished - Mar 6 2015
Externally publishedYes

Fingerprint

STAT3 Transcription Factor
Helicobacter pylori
Interleukin-10
Dendritic Cells
Bone Marrow
Helicobacter Infections
Interleukin-1
Infection
Urease
Immunosuppressive Agents
Gastric Mucosa
Innate Immunity
Transcriptional Activation
Stomach Neoplasms
Carcinogenesis
Cytokines
Bacteria

Keywords

  • Bacteriology
  • Cytokines
  • Dendritic cells
  • H. pylori
  • Immune response

ASJC Scopus subject areas

  • Immunology and Allergy

Cite this

Helicobacter pylori inhibits dendritic cell maturation via interleukin-10-mediated activation of the signal transducer and activator of transcription 3 pathway. / Rizzuti, David; Ang, Michelle; Sokollik, Christiane; Wu, Ted; Abdullah, Majd; Greenfield, Laura; Fattouh, Ramzi; Reardon, Colin; Tang, Michael; Diao, Jun; Schindler, Christian; Cattral, Mark; Jones, Nicola L.

In: Journal of Innate Immunity, Vol. 7, No. 2, 06.03.2015, p. 199-211.

Research output: Contribution to journalArticle

Rizzuti, D, Ang, M, Sokollik, C, Wu, T, Abdullah, M, Greenfield, L, Fattouh, R, Reardon, C, Tang, M, Diao, J, Schindler, C, Cattral, M & Jones, NL 2015, 'Helicobacter pylori inhibits dendritic cell maturation via interleukin-10-mediated activation of the signal transducer and activator of transcription 3 pathway', Journal of Innate Immunity, vol. 7, no. 2, pp. 199-211. https://doi.org/10.1159/000368232
Rizzuti, David ; Ang, Michelle ; Sokollik, Christiane ; Wu, Ted ; Abdullah, Majd ; Greenfield, Laura ; Fattouh, Ramzi ; Reardon, Colin ; Tang, Michael ; Diao, Jun ; Schindler, Christian ; Cattral, Mark ; Jones, Nicola L. / Helicobacter pylori inhibits dendritic cell maturation via interleukin-10-mediated activation of the signal transducer and activator of transcription 3 pathway. In: Journal of Innate Immunity. 2015 ; Vol. 7, No. 2. pp. 199-211.
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abstract = "Helicobacter pylori infects the human gastric mucosa causing a chronic infection that is the primary risk factor for gastric cancer development. Recent studies demonstrate that H. pylori promotes tolerogenic dendritic cell (DC) development indicating that this bacterium evades the host immune response. However, the signaling pathways involved in modulating DC activation during infection remain unclear. Here, we report that H. pylori infection activated the signal transducer and activator of transcription 3 (STAT3) pathway in murine bone marrow-derived DCs (BMDCs) and splenic DCs isolated ex vivo. Isogenic cagA-, cagE-, vacA- and urease-mutants exhibited levels of phosphoSTAT3 that were comparable to in the wild-type (WT) parent strain. H. pylori-infected BMDCs produced increased immunosuppressive IL-10, which activated STAT3 in an autocrine/paracrine fashion. Neutralization of IL-10 prevented H. pylori-mediated STAT3 activation in both BMDCs and splenic DCs. In addition, anti-IL-10 treatment of infected H. pylori-BMDCs was associated with increased CD86 and MHC II expression and enhanced proinflammatory IL-1β cytokine secretion. Finally, increased CD86 and MHC II expression was detected in H. pylori-infected STAT3 knockout DCs when compared to WT controls. Together, these results demonstrate that H. pylori infection induces IL-10 secretion in DCs, which activates STAT3, thereby modulating DC maturation and reducing IL-1β secretion. These findings identify a host molecular mechanism by which H. pylori can manipulate the innate immune response to potentially favor chronic infection and promote carcinogenesis.",
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AU - Ang, Michelle

AU - Sokollik, Christiane

AU - Wu, Ted

AU - Abdullah, Majd

AU - Greenfield, Laura

AU - Fattouh, Ramzi

AU - Reardon, Colin

AU - Tang, Michael

AU - Diao, Jun

AU - Schindler, Christian

AU - Cattral, Mark

AU - Jones, Nicola L.

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N2 - Helicobacter pylori infects the human gastric mucosa causing a chronic infection that is the primary risk factor for gastric cancer development. Recent studies demonstrate that H. pylori promotes tolerogenic dendritic cell (DC) development indicating that this bacterium evades the host immune response. However, the signaling pathways involved in modulating DC activation during infection remain unclear. Here, we report that H. pylori infection activated the signal transducer and activator of transcription 3 (STAT3) pathway in murine bone marrow-derived DCs (BMDCs) and splenic DCs isolated ex vivo. Isogenic cagA-, cagE-, vacA- and urease-mutants exhibited levels of phosphoSTAT3 that were comparable to in the wild-type (WT) parent strain. H. pylori-infected BMDCs produced increased immunosuppressive IL-10, which activated STAT3 in an autocrine/paracrine fashion. Neutralization of IL-10 prevented H. pylori-mediated STAT3 activation in both BMDCs and splenic DCs. In addition, anti-IL-10 treatment of infected H. pylori-BMDCs was associated with increased CD86 and MHC II expression and enhanced proinflammatory IL-1β cytokine secretion. Finally, increased CD86 and MHC II expression was detected in H. pylori-infected STAT3 knockout DCs when compared to WT controls. Together, these results demonstrate that H. pylori infection induces IL-10 secretion in DCs, which activates STAT3, thereby modulating DC maturation and reducing IL-1β secretion. These findings identify a host molecular mechanism by which H. pylori can manipulate the innate immune response to potentially favor chronic infection and promote carcinogenesis.

AB - Helicobacter pylori infects the human gastric mucosa causing a chronic infection that is the primary risk factor for gastric cancer development. Recent studies demonstrate that H. pylori promotes tolerogenic dendritic cell (DC) development indicating that this bacterium evades the host immune response. However, the signaling pathways involved in modulating DC activation during infection remain unclear. Here, we report that H. pylori infection activated the signal transducer and activator of transcription 3 (STAT3) pathway in murine bone marrow-derived DCs (BMDCs) and splenic DCs isolated ex vivo. Isogenic cagA-, cagE-, vacA- and urease-mutants exhibited levels of phosphoSTAT3 that were comparable to in the wild-type (WT) parent strain. H. pylori-infected BMDCs produced increased immunosuppressive IL-10, which activated STAT3 in an autocrine/paracrine fashion. Neutralization of IL-10 prevented H. pylori-mediated STAT3 activation in both BMDCs and splenic DCs. In addition, anti-IL-10 treatment of infected H. pylori-BMDCs was associated with increased CD86 and MHC II expression and enhanced proinflammatory IL-1β cytokine secretion. Finally, increased CD86 and MHC II expression was detected in H. pylori-infected STAT3 knockout DCs when compared to WT controls. Together, these results demonstrate that H. pylori infection induces IL-10 secretion in DCs, which activates STAT3, thereby modulating DC maturation and reducing IL-1β secretion. These findings identify a host molecular mechanism by which H. pylori can manipulate the innate immune response to potentially favor chronic infection and promote carcinogenesis.

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