Helicobacter pylori Activates HMGB1 Expression and Recruits RAGE into Lipid Rafts to Promote Inflammation in Gastric Epithelial Cells.
Helicobacter pylori infection is associated with several gastrointestinal disorders in the human population worldwide. High-mobility group box 1 (HMGB1), a ubiquitous nuclear protein, mediates various inflammation functions. The interaction between HMGB1 and receptor for advanced glycation end-products (RAGE) triggers nuclear factor (NF)-κB expression, which in turn stimulates the release of proinflammatory cytokines, such as interleukin (IL)-8, and enhances the inflammatory response. However, how H. pylori activates HMGB1 expression and mobilizes RAGE into cholesterol-rich microdomains in gastric epithelial cells to promote inflammation has not been explored. In this study, we found that HMGB1 and RAGE expression increased significantly in H. pylori-infected cells compared with -uninfected cells. Blocking HMGB1 by neutralizing antibody abrogated H. pylori-elicited RAGE, suggesting that RAGE expression follows HMGB1 production, and silenced RAGE-attenuated H. pylori-mediated NF-κB activation and IL-8 production. Furthermore, significantly more RAGE was present in detergent-resistant membranes extracted from H. pylori-infected cells than in those from -uninfected cells, indicating that H. pylori exploited cholesterol to induce the HMGB1 signaling pathway. These results indicate that HMGB1 plays a crucial role in H. pylori-induced inflammation in gastric epithelial cells, which may be valuable in developing treatments for H. pylori-associated diseases.
Department of Internal Medicine, Division of Gastroenterology and Hepatology, College of Medicine, School of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Internal Medicine, Division of Gastroenterology and Hepatology, Shuang-Ho Hospital, New Taipei, Taiwan.
Hwai-Jeng
HJ
Lin
Graduate Institute of Basic Medical Science, School of Medicine, China Medical University , Taichung , Taiwan.
Fang-Yu
FY
Hsu
Graduate Institute of Basic Medical Science, School of Medicine, China Medical University , Taichung , Taiwan.
Wei-Wei
WW
Chen
Graduate Institute of Basic Medical Science, School of Medicine, China Medical University, Taichung, Taiwan; Department of Biological Sciences, National Sun Yet-sen University, Kaohsiung, Taiwan.
Che-Hsin
CH
Lee
Department of Medical Research, Genetic Center, School of Chinese Medicine, China Medical University and Hospital , Taichung , Taiwan.
Ying-Ju
YJ
Lin
Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan; Department of Pediatrics, Molecular Infectious Disease Research Center, Chang Gung Children's Hospital and Chang Gung Memorial Hospital, Taoyuan, Taiwan.
Yi-Ywan M
YY
Chen
Department of Pediatrics, Molecular Infectious Disease Research Center, Chang Gung Children's Hospital and Chang Gung Memorial Hospital , Taoyuan , Taiwan.
Chih-Jung
CJ
Chen
Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung University , Taoyuan , Taiwan.
Mei-Zi
MZ
Huang
Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung University , Taoyuan , Taiwan.
Min-Chuan
MC
Kao
Graduate Institute of Basic Medical Science, School of Medicine, China Medical University , Taichung , Taiwan.
Yu-An
YA
Chen
Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan, Taiwan; Department of Laboratory Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
Hsin-Chih
HC
Lai
Graduate Institute of Basic Medical Science, School of Medicine, China Medical University, Taichung, Taiwan; Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan; Department of Pediatrics, Molecular Infectious Disease Research Center, Chang Gung Children's Hospital and Chang Gung Memorial Hospital, Taoyuan, Taiwan; Department of Nursing, Asia University, Taichung, Taiwan.
Chih-Ho
CH
Lai
HMGB1; Helicobacter pylori; RAGE; cholesterol; interleukin-8
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