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Updated: Jul 31, 2025
Mouse Models Of Helicobacter Infection And Gastric Pathologies
Published on: October 18, 2018
Induction of MMP-3 and MMP-9 expression during Helicobacter pylori infection via MAPK signaling pathways
Ioannis Karayiannis1,2, Beatriz Martinez-Gonzalez1, Eleftherios Kontizas1
1Laboratory of Medical Microbiology, Hellenic Pasteur Institute, Athens, Greece.
Background And Aims:
Helicobacter pylori (H. pylori)-induced gastric pathology involves remodeling of extracellular matrix mediated by aberrant activity of matrix metalloproteinases (MMPs). We have previously shown that in vitro H. pylori infection leads to MMP-3 and MMP-9 overexpression, associated with phosphorylation of bacterial oncoprotein CagA. We extended these findings in an in vivo model of H. pylori infection and further assessed the involvement of MAPK pathways in MMP expression.
Materials And Methods:
C57BL/6 mice were infected with H. pylori strains HPARE, HPARE ΔCagA, and SS1, for 6 and 9 months. Transcriptional expression of Mmp-3 and Mmp-9 was evaluated via qPCR while respective protein levels in the gastric mucosa were determined immunohistochemically. Epithelial cell lines AGS and GES-1 were infected with H. pylori strain P12 in the presence of chemical inhibitors of JNK, ERK1/2, and p38 pathways, for 24 h. mRNA and protein expression of MMP-3 and MMP-9 were determined via qPCR and Western blot, respectively.
Results:
We observed transcriptional activation of Mmp-3 and Mmp-9 as well as aberrant MMP-3 and MMP-9 protein expression in murine gastric tissue following H. pylori infection. CagA expression was associated with MMP upregulation, particularly during the early time points of infection. We found that inhibition of ERK1/2 resulted in reduced mRNA and protein expression of MMP-3 and MMP-9 during H. pylori infection, in both cell lines. Expressed protein levels of both MMPs were also found reduced in the presence of JNK pathway inhibitors in both cell lines. However, p38 inhibition resulted in a more complex effect, probably attributed to the accumulation of phospho-p38 and increased phospho-ERK1/2 activity due to crosstalk between MAPK pathways.
Conclusions:
H. pylori colonization leads to the upregulation of MMP-3 and MMP-9 in vivo, which primarily involves ERK1/2 and JNK pathways. Therefore, their inhibition may potentially offer a protective effect against gastric carcinogenesis and metastasis.
Insights
Helicobacter pylori infection upregulates matrix metalloproteinases (MMPs) in the stomach, involving CagA and MAPK pathways. Inhibiting ERK1/2 and JNK may prevent gastric cancer and metastasis.
Area of Science:
- Gastroenterology
- Molecular Biology
- Oncology
Background:
- Helicobacter pylori (H. pylori) infection causes gastric pathology through extracellular matrix remodeling.
- Aberrant matrix metalloproteinase (MMP) activity, specifically MMP-3 and MMP-9, is implicated in H. pylori-induced gastric disease.
- Previous in vitro studies linked H. pylori infection and CagA phosphorylation to MMP overexpression.
Purpose of the Study:
- To investigate the in vivo effects of H. pylori infection on MMP-3 and MMP-9 expression in a murine model.
- To elucidate the role of mitogen-activated protein kinase (MAPK) pathways (JNK, ERK1/2, p38) in H. pylori-mediated MMP upregulation.
Main Methods:
- Infection of C57BL/6 mice with H. pylori strains for 6-9 months.
- Quantitative PCR (qPCR) to assess Mmp-3 and Mmp-9 transcriptional expression.
- Immunohistochemistry to determine MMP-3 and MMP-9 protein levels in gastric mucosa.
- In vitro infection of epithelial cell lines (AGS, GES-1) with H. pylori in the presence of MAPK pathway inhibitors (JNK, ERK1/2, p38).
- Western blot analysis for protein expression.
Main Results:
- H. pylori infection induced Mmp-3 and Mmp-9 transcription and protein expression in murine gastric tissue.
- CagA expression correlated with MMP upregulation, especially early in infection.
- Inhibition of ERK1/2 and JNK pathways reduced MMP-3 and MMP-9 mRNA and protein levels in H. pylori-infected cell lines.
- p38 inhibition showed complex effects, potentially due to pathway crosstalk.
Conclusions:
- H. pylori colonization upregulates MMP-3 and MMP-9 in vivo.
- The ERK1/2 and JNK pathways are primarily involved in this MMP upregulation.
- Targeting these pathways could offer a protective strategy against H. pylori-associated gastric carcinogenesis and metastasis.
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