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Background <p><i>Helicobacter pylori</i> (Hp) infection is the primary cause of gastric cancer. We previously demonstrated that TRAF1 expression was significantly increased during the multistep pathological timeline of Correa’s cascade and that these changes were closely correlated with Hp virulence factor VacA. However, the underlying mechanism remains unknown.</p> Methods <p>TRAF1-deficient or overexpressing human gastric mucosal epithelial cells were generated, and wild-type/<i>vacA</i>-KO mutant Hp, recombinant VacA protein and pDsRED2-N1-HA/VacA plasmid were used for mechanistic investigation of VacA. In addition, we established mice infection models and evaluated gastric pathological changes.</p> Results <p>RNA sequencing and cellular experiments suggested that positive correlations between TRAF1 expression and NF-κB pathway activation and apoptosis. VacA increased the protein levels of TRAF1, 4-1BB, p-IKKα/β, phosphorylated p65, Bax, and the downstream inflammatory factor IL-8 but reduced that of Bcl-xl, promoting apoptosis and inhibiting proliferation in vitro. Transient and stable overexpression of TRAF1 promoted VacA-induced 4-1BB expression, NF-κB pathways activation, apoptosis-related molecules levels, and downstream inflammatory factors secretion in gastric epithelial cells, whereas silencing of TRAF1 led to the opposite effects. Functionally, TRAF1 increased VacA-induced p65 nuclear translocation and transcriptional activity, leading to apoptosis. BAY11-7082 (an NF-κB inhibitor) or 4-1BB blocking antibody attenuated the promotive effect of TRAF1 overexpression on VacA-induced NF-κB pathway activation, apoptosis-related protein expression, and downstream inflammatory factors secretion in gastric epithelial cells, whereas 4-1BB agonist antibody reversed the inhibitory effect of TRAF1 silencing on VacA function. In vivo, the immunofluorescence of TRAF1, 4-1BB and NF-κB p65 at <i>vacA</i><sup>+</sup>Hp colonization sites was increased, and TRAF1 expression increased gradually with prolonged infection, correlating with exacerbated gastric mucosal inflammation and damage. Hp eradication or BAY11-7082 treatment reversed TRAF1 expression in mouse mucosal tissue.</p> Conclusions <p>We revealed a novel VacA–TRAF1–NF-κB pathway–IL-8 signalling axis, exposing novel connections among Hp infection, inflammation and gastric tumorigenesis.</p> Graphical Abstract <p></p>

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Helicobacter pylori VacA modulates TRAF1-mediated 4-1BB/NF-kappaB axis to induce host apoptosis and chronic inflammatory damage

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月24日

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  • Lingzhi Yuan,
  • Shuoyi Yao,
  • Nanfang Qu,
  • Xinmeng Li,
  • Xueer Yang,
  • Aojian Deng,
  • Minglin Zhang,
  • Ting Cai,
  • Lunxi Liang,
  • Zhitao Liu,
  • Xiaoming Liu,
  • Fen Wang

摘要

Background

Helicobacter pylori (Hp) infection is the primary cause of gastric cancer. We previously demonstrated that TRAF1 expression was significantly increased during the multistep pathological timeline of Correa’s cascade and that these changes were closely correlated with Hp virulence factor VacA. However, the underlying mechanism remains unknown.

Methods

TRAF1-deficient or overexpressing human gastric mucosal epithelial cells were generated, and wild-type/vacA-KO mutant Hp, recombinant VacA protein and pDsRED2-N1-HA/VacA plasmid were used for mechanistic investigation of VacA. In addition, we established mice infection models and evaluated gastric pathological changes.

Results

RNA sequencing and cellular experiments suggested that positive correlations between TRAF1 expression and NF-κB pathway activation and apoptosis. VacA increased the protein levels of TRAF1, 4-1BB, p-IKKα/β, phosphorylated p65, Bax, and the downstream inflammatory factor IL-8 but reduced that of Bcl-xl, promoting apoptosis and inhibiting proliferation in vitro. Transient and stable overexpression of TRAF1 promoted VacA-induced 4-1BB expression, NF-κB pathways activation, apoptosis-related molecules levels, and downstream inflammatory factors secretion in gastric epithelial cells, whereas silencing of TRAF1 led to the opposite effects. Functionally, TRAF1 increased VacA-induced p65 nuclear translocation and transcriptional activity, leading to apoptosis. BAY11-7082 (an NF-κB inhibitor) or 4-1BB blocking antibody attenuated the promotive effect of TRAF1 overexpression on VacA-induced NF-κB pathway activation, apoptosis-related protein expression, and downstream inflammatory factors secretion in gastric epithelial cells, whereas 4-1BB agonist antibody reversed the inhibitory effect of TRAF1 silencing on VacA function. In vivo, the immunofluorescence of TRAF1, 4-1BB and NF-κB p65 at vacA+Hp colonization sites was increased, and TRAF1 expression increased gradually with prolonged infection, correlating with exacerbated gastric mucosal inflammation and damage. Hp eradication or BAY11-7082 treatment reversed TRAF1 expression in mouse mucosal tissue.

Conclusions

We revealed a novel VacA–TRAF1–NF-κB pathway–IL-8 signalling axis, exposing novel connections among Hp infection, inflammation and gastric tumorigenesis.

Graphical Abstract