Molecular Medicine | VacA Induces Gastric Epithelial Cell Apoptosis and Chronic Inflammation via the TRAF1-4-1BB-NF-κB-IL-8 Axis

This study reveals a novel mechanism by which Helicobacter pylori virulence factor VacA induces gastric epithelial cell apoptosis and chronic inflammation through regulation of TRAF1 and its downstream 4-1BB/NF-κB signaling axis, providing new molecular insights for gastric cancer pathogenesis.

 

Literature Overview
This article, 'VacA modulates TRAF1-mediated 4-1BB/NF-κB axis to induce host apoptosis and chronic inflammatory damage', published in Molecular Medicine, reviews and summarizes the mechanistic role of Helicobacter pylori (Hp) virulence factor VacA in regulating 4-1BB and NF-κB signaling pathways through TRAF1 in gastric epithelial cells, leading to apoptosis and inflammatory responses. The research team further validated the functional conservation of this pathway in mouse models and investigated dynamic TRAF1 expression changes during infection.

Background Knowledge
Helicobacter pylori (Hp) infection is a major risk factor for gastric cancer. Its virulence factor VacA induces gastric epithelial apoptosis and inflammation through multiple mechanisms. TRAF1, a regulatory factor of the NF-κB pathway, has been associated with gastric cancer development following Hp infection. While VacA's mitochondrial pathway interactions have been studied, its potential regulation of NF-κB and downstream inflammatory factors like IL-8 through TRAF1 remains unclear. This study systematically characterizes VacA-TRAF1 signaling crosstalk using diverse cell and animal models, identifying new molecular targets for gastric cancer pathogenesis.

 

 

Research Methods and Experiments
The study employed human gastric mucosal epithelial cell lines (GES-1, HGC27, MKN74) with stable or transient TRAF1 overexpression/knockdown models, combined with wild-type and vacA-knockout Hp strains and recombinant VacA protein for infection assays. RNA sequencing, Western blot, qRT-PCR, immunofluorescence, ELISA, and flow cytometry were used to analyze expression changes in TRAF1, 4-1BB, NF-κB pathway components, apoptosis-related proteins, and inflammatory factors (e.g., IL-8). Mouse infection models were established to evaluate VacA/TRAF1 effects on NF-κB nuclear translocation, gastric pathology, and TRAF1 expression reversal after Hp clearance.

Key Conclusions and Perspectives

• TRAF1 expression positively correlates with NF-κB activation and apoptosis. VacA significantly upregulates TRAF1, 4-1BB, p-IKKα/β, p-p65, Bax, and IL-8 while downregulating Bcl-xl.
• Stable TRAF1 overexpression enhances VacA-induced 4-1BB/NF-κB activation and apoptosis-related protein expression, whereas TRAF1 knockdown shows opposing effects.
• TRAF1 promotes VacA-induced p65 nuclear translocation and transcriptional activity; these effects are attenuated by the NF-κB inhibitor BAY11-7082 or 4-1BB blocking antibodies.
• Mouse infection models demonstrate elevated TRAF1, 4-1BB, and NF-κB p65 expression at VacA⁺-Hp colonization sites, with TRAF1 expression increasing over time and correlating with gastric tissue damage severity.
• TRAF1 expression in mouse gastric mucosa is reversible upon Hp clearance or BAY11-7082 treatment, highlighting the NF-κB pathway's critical role in VacA-TRAF1 signaling.

Research Significance and Prospects
This work establishes the VacA–TRAF1–NF-κB–IL-8 signaling axis as a potential driver of gastric cancer pathogenesis, offering novel targets for early diagnosis and therapeutic intervention. Future studies should investigate this pathway's dynamic behavior across gastric cancer stages and evaluate its feasibility as a clinical treatment target.

 

 

Conclusion
In summary, this study systematically elucidates a previously unrecognized mechanism where Helicobacter pylori virulence factor VacA induces gastric epithelial apoptosis and chronic inflammation through TRAF1-mediated regulation of the 4-1BB/NF-κB pathway. This discovery not only advances molecular understanding of Hp-associated gastric carcinogenesis but also identifies potential targets for therapeutic intervention. The mouse infection model confirms TRAF1's central role in VacA-induced gastric injury, providing a foundation for in vivo target validation and drug development.

 

Lingzhi Yuan, Shuoyi Yao, Nanfang Qu, Xiaoming Liu, and Fen Wang. Helicobacter pylori VacA modulates TRAF1-mediated 4-1BB/NF-kappaB axis to induce host apoptosis and chronic inflammatory damage. Molecular Medicine.