title: Helicobacter pylori inhibits dendritic cell maturation via interleukin-10-mediated activation of the signal transducer and activator of transcription 3 pathway.
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.
authors.affiliation: Departments of Paediatrics and Physiology, University of Toronto, Toronto, Ont., Canada.
authors.forename: David
authors.initials: D
authors.lastname: Rizzuti
authors.forename: Michelle
authors.initials: M
authors.lastname: Ang
authors.forename: Christiane
authors.initials: C
authors.lastname: Sokollik
authors.forename: Ted
authors.initials: T
authors.lastname: Wu
authors.forename: Majd
authors.initials: M
authors.lastname: Abdullah
authors.forename: Laura
authors.initials: L
authors.lastname: Greenfield
authors.forename: Ramzi
authors.initials: R
authors.lastname: Fattouh
authors.forename: Colin
authors.initials: C
authors.lastname: Reardon
authors.forename: Michael
authors.initials: M
authors.lastname: Tang
authors.forename: Jun
authors.initials: J
authors.lastname: Diao
authors.forename: Christian
authors.initials: C
authors.lastname: Schindler
authors.forename: Mark
authors.initials: M
authors.lastname: Cattral
authors.forename: Nicola L
authors.initials: NL
authors.lastname: Jones
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D016481:Helicobacter Infections / Q000276:immunology*; D016480:Helicobacter pylori / Q000276:immunology*; D006801:Humans; D057131:Immune Evasion / Q000187:drug effects; D007113:Immunity, Innate / Q000187:drug effects; D016753:Interleukin-10 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D019138:Antibodies, Blocking; D053583:Interleukin-1beta; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016753:Interleukin-10