Regulatory and functional mechanism of angiopoietin-like protein-4 in gastric epithelial cells with Helicobacter pylori infection

Abstract

Objective To explore the regulatory and functional mechanism of angiopoietin-like 4 (ANGPTL4) expression in gastric epithelial cells infected with Helicobacter pylori (H.pylori). Methods H.pylori-positive gastric specimens from Department of Gastroenterology of second Affiliated Hospital of Army Medical University in November 2021 and the gastric tissues of H.pylori-infected mice were collected, and the expression locations of ANGPTL4 in these gastric tissues were detected by immunofluorescence assay. After gastric epithelial cells and gastric organoids were infected with H.pylori, the expression of ANGPTL4 was detected by real-time PCR and Western blotting. The regulatory mechanism of H.pylori-induced ANGPTL4 expression was investigated by cellular models above. Recombinant ANGPTL4 was used to stimulate gastric epithelial cells to investigate the effect of ANGPTL4 on the claudin 1 (CLDN1) expression. Results H.pylori infection significantly increased the expression of ANGPTL4 in gastric epithelial cells in a CagA-dependent, bacterial concentration-dependent and infection time-dependent manner (P < 0.05). Compared to uninfected cells and CagA knockout (△cagA) H.pylori-induced ones, the ANGPTL4 expression was significantly increased in WT H.pylori-infected human and mouse gastric organoid (P < 0.05). Blocking NF-κB signaling pathway significantly inhibited the enhanced ANGPTL4 expression in H.pylori-infected gastric epithelial cells (P < 0.05). Recombinant ANGPTL4 activated ERK signaling pathway to down-regulate the CLDN1 expression in gastric epithelial cells (P < 0.05). Conclusion H.pylori activates NF-κB signaling pathway to up-regulate ANGPTL4 expression in gastric epithelial cells in a CagA-dependent manner, and ANGPTL4 activates ERK signaling pathway to down-regulate the CLDN1 expression in gastric epithelial cells, which may contributes to the development of gastric diseases induced by H.pylori infection.

Keywords

• helicobacter pylori
• angiopoietin-like 4
• nf-κb
• claudin 1