PUMA-mediated epithelial cell apoptosis promotes Helicobacter pylori infection-mediated gastritis

• Published in: Cell death & disease Vol. 11; no. 2; p. 139
• Main Authors: Dang, Yini, Zhang, Yifeng, Xu, Lingyan, Zhou, Xiaoying, Gu, Yanhong, Yu, Jian, Jin, Shidai, Ji, Haoming, Shu, Yongqian, Zhang, Guoxin, Cui, Shiyun, Sun, Jing
• Format: Journal Article
• Language: English
• Published: England Springer Nature B.V 20.02.2020; Nature Publishing Group UK
• Subjects: Animals; Apoptosis; Apoptosis Regulatory Proteins - deficiency; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Bcl-2 protein; Carcinogenesis; Cell Line, Tumor; Disease Models, Animal; Epithelial cells; Epithelial Cells - metabolism; Epithelial Cells - microbiology; Epithelial Cells - pathology; Gastric cancer; Gastric Mucosa - metabolism; Gastric Mucosa - microbiology; Gastric Mucosa - pathology; Gastritis; Gastritis - genetics; Gastritis - metabolism; Gastritis - microbiology; Gastritis - pathology; Gene regulation; Health risk assessment; Helicobacter Infections - genetics; Helicobacter Infections - metabolism; Helicobacter Infections - microbiology; Helicobacter Infections - pathology; Helicobacter pylori; Helicobacter pylori - pathogenicity; Humans; Infections; Inflammation; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B - metabolism; NF-κB protein; Proto-Oncogene Proteins - deficiency; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Signal Transduction; TLR2 protein; Toll-Like Receptor 2 - genetics; Toll-Like Receptor 2 - metabolism; Toll-like receptors; Tumor Suppressor Proteins - deficiency; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-2339-x

The molecular mechanism responsible for Helicobacter pylori infection-mediated gastritis and carcinogenesis is not yet clear. Increased evidence suggests that chronic gastritis and elevated gastric epithelial cell (GEC) apoptosis are crucial events during stomach carcinoma transformation. PUMA is a potent proapoptotic Bcl-2 protein and mediates acute tissue injury. In this study, we aimed to investigate the role of PUMA in GEC apoptosis and inflammation induced by H. pylori infection. As a result, we found that PUMA expression was elevated in gastritis tissues compared with uninvolved tissues, and it was correlated with the severity of apoptosis and gastritis. In mice, PUMA mRNA and protein were markedly induced in GECs upon induction of gastritis by H. pylori. PUMA-deficient mice were highly resistant to apoptosis and gastritis induced by H. pylori. Furthermore, the transcription factor NF-κB p65 binds to PUMA promoter to activate PUMA transcription after H. pylori infection. In addition, NF-κB inhibitor could rescue H. pylori-induced apoptosis and gastritis. Finally, H. pylori-induced activation of p-p65 and PUMA was mediated via Toll-like receptor 2 (TLR2) and blocked in TLR2 knockout mice. Taken together, these results verified the pro-inflammatory effect of PUMA in H. pylori-infected gastric tissue. Moreover, TLR2/NF-κB-mediated transcriptional regulation of PUMA contributes to the pathogenesis of H. pylori-infected gastritis.