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Helicobacter pylori-induced Sonic Hedgehog expression is regulated by NF?B pathway activation: the use of a novel in vitro model to study epithelial response to infection.

ABSTRACT: Helicobacter pylori (H. pylori) infection leads to acute induction of Sonic Hedgehog (Shh) in the stomach that is associated with the initiation of gastritis. The mechanism by which H. pylori induces Shh is unknown. Shh is a target gene of transcription factor Nuclear Factor-?B (NF?B). We hypothesize that NF?B mediates H. pylori-induced Shh.To visualize Shh ligand expression in response to H. pylori infection in vivo, we used a mouse model that expresses Shh fused to green fluorescent protein (Shh::GFP mice) in place of wild-type Shh. In vitro, changes in Shh expression were measured in response to H. pylori infection using 3-dimensional epithelial cell cultures grown from whole dissociated gastric glands (organoids). Organoids were generated from stomachs collected from the fundic region of control and mice expressing a parietal cell-specific deletion of Shh (PC-Shh(KO) mice).Within 2 days of infection, H. pylori induced Shh expression within parietal cells of Shh::GFP mice. Organoids expressed all major gastric cell markers, including parietal cell marker H(+) ,K(+) -ATPase and Shh. H. pylori infection of gastric organoids induced Shh expression; a response that was blocked by inhibiting NF?B signaling and correlated with I?B degradation. H. pylori infection of PC-Shh(KO) mouse-derived organoids did not result in the induction of Shh expression.Gastric organoids allow for the study of the interaction between H. pylori and the differentiated gastric epithelium independent of the host immune response. H. pylori induces Shh expression from the parietal cells, a response mediated via activation of NF?B signaling.

SUBMITTER: Schumacher MA

PROVIDER: S-EPMC4871133 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Helicobacter pylori-induced Sonic Hedgehog expression is regulated by NFκB pathway activation: the use of a novel in vitro model to study epithelial response to infection.

Schumacher Michael A MA Feng Rui R Aihara Eitaro E Engevik Amy C AC Montrose Marshall H MH Ottemann Karen M KM Zavros Yana Y

Helicobacter 20141211 1

<h4>Background</h4>Helicobacter pylori (H. pylori) infection leads to acute induction of Sonic Hedgehog (Shh) in the stomach that is associated with the initiation of gastritis. The mechanism by which H. pylori induces Shh is unknown. Shh is a target gene of transcription factor Nuclear Factor-κB (NFκB). We hypothesize that NFκB mediates H. pylori-induced Shh.<h4>Materials and methods</h4>To visualize Shh ligand expression in response to H. pylori infection in vivo, we used a mouse model that ex ...[more]

PMID: 25495001

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Project description:Helicobacter pylori infection of gastric tissue results in an immune response dominated by Th1 cytokines and has also been linked with dysregulation of Sonic Hedgehog (SHH) signaling pathway in gastric tissue. However, since interactions between the cytokines and SHH during H. pylori infection are not well understood, any mechanistic understanding achieved through interpretation of the statistical analysis of experimental results in the context of currently known circuit must be carefully scrutinized. Here, we use mathematical modeling aided by restraints of experimental data to evaluate the consistency between experimental results and temporal behavior of H. pylori activated cytokine circuit model. Statistical analysis of qPCR data from uninfected and H. pylori infected wild-type and parietal cell-specific SHH knockout (PC-SHHKO) mice for day 7 and 180 indicate significant changes that suggest role of SHH in cytokine regulation. The experimentally observed changes are further investigated using a mathematical model that examines dynamic crosstalks among pro-inflammatory (IL1?, IL-12, IFN?, MIP-2) cytokines, anti-inflammatory (IL-10) cytokines and SHH during H. pylori infection. Response analysis of the resulting model demonstrates that circuitry, as currently known, is inadequate for explaining of the experimental observations; suggesting the need for additional specific regulatory interactions. A key advantage of a computational model is the ability to propose putative circuit models for in-silico experimentation. We use this approach to propose a parsimonious model that incorporates crosstalks between NF?B, SHH, IL-1? and IL-10, resulting in a feedback loop capable of exhibiting cyclic behavior. Separately, we show that analysis of an independent time-series GEO microarray data for IL-1?, IFN? and IL-10 in mock and H. pylori infected mice further supports the proposed hypothesis that these cytokines may follow a cyclic trend. Predictions from the in-silico model provide useful insights for generating new hypothesis and design of subsequent experimental studies.

Dataset Information

Helicobacter pylori-induced Sonic Hedgehog expression is regulated by NF?B pathway activation: the use of a novel in vitro model to study epithelial response to infection.

Publications

Helicobacter pylori-induced Sonic Hedgehog expression is regulated by NFκB pathway activation: the use of a novel in vitro model to study epithelial response to infection.

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