CagA-dependent expression of anti-inflammatory cytokine IL-13 and TNFRSF member Fn14 in Helicobacter pylori infected gastric cells and tissues

Helicobacter pylori infection is a major driver of gastric cancer, with the CagA oncoprotein promoting chronic inflammation and epithelial injury. However, the overall picture of the cytokine–receptor pathways involved in this process remains unclear. To investigate how CagA modulates epithelial signaling, we generated cagA -deletion and cagA -complemented mutants of the gerbil-adapted TN2 strain and infected AGS gastric epithelial cells for 6–48 h. We also analyzed 85 gastric biopsy specimens from a nationwide Indonesian survey. In vitro , wild-type and cagA -complemented H. pylori robustly induced IL-8, IL-1β, and TNF-α, as expected. In the CagA-positive strain, the newly identified anti-inflammatory cytokine, IL-13, was also induced. IL-13-related Fn14, a TNF receptor superfamily member, was strongly upregulated in a CagA-positive strain, whereas TNFR1 remained stable, and TNFR2 was consistently downregulated. In clinical specimens, Fn14 expression was elevated in atrophic gastritis and closely associated with cagA positivity. IL-13 expression showed a distinct pattern, increased in atrophic gastritis but unrelated to H. pylori or cagA status, instead correlating positively with TWEAK, the ligand for Fn14. Together, these findings suggest that cagA-positive H. pylori infection is associated with Fn14 upregulation, whereas H. pylori infection in general is linked to TNFR2 downregulation. IL-13-related signaling may instead reflect mucosal injury and repair responses, indicating context-dependent regulation of TNF receptor family pathways in gastric mucosal inflammation.