title: Helicobacter pylori infection activates Src homology-2 domain-containing phosphatase 2 to suppress IFN-γ signaling.
abstract: Helicobacter pylori infection not only induces gastric inflammation but also increases the risk of gastric tumorigenesis. IFN-γ has antimicrobial effects; however, H. pylori infection elevates IFN-γ-mediated gastric inflammation and may suppress IFN-γ signaling as a strategy to avoid immune destruction through an as-yet-unknown mechanism. This study was aimed at investigating the mechanism of H. pylori-induced IFN-γ resistance. Postinfection of viable H. pylori decreased IFN-γ-activated signal transducers and activators of transcription 1 and IFN regulatory factor 1 not only in human gastric epithelial MKN45 and AZ-521 but also in human monocytic U937 cells. H. pylori caused an increase in the C-terminal tyrosine phosphorylation of Src homology-2 domain-containing phosphatase (SHP) 2. Pharmacologically and genetically inhibiting SHP2 reversed H. pylori-induced IFN-γ resistance. In contrast to a clinically isolated H. pylori strain HP238, the cytotoxin-associated gene A (CagA) isogenic mutant strain HP238(CagAm) failed to induce IFN-γ resistance, indicating that CagA regulates this effect. Notably, HP238 and HP238(CagAm) differently caused SHP2 phosphorylation; however, imaging and biochemical analyses demonstrated CagA-mediated membrane-associated binding with phosphorylated SHP2. CagA-independent generation of reactive oxygen species (ROS) contributed to H. pylori-induced SHP2 phosphorylation; however, ROS/SHP2 mediated IFN-γ resistance in a CagA-regulated manner. This finding not only provides an alternative mechanism for how CagA and ROS coregulate SHP2 activation but may also explain their roles in H. pylori-induced IFN-γ resistance.
authors.affiliation: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; Department of Microbiology and Immunology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan;
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Center of Translational Medicine, Taipei Medical University, Taipei 110, Taiwan;
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan;
authors.forename: Bor-Shyang
authors.initials: BS
authors.lastname: Sheu
authors.affiliation: Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan;
authors.forename: Yao-Jong
authors.initials: YJ
authors.lastname: Yang
authors.affiliation: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan;
authors.forename: Po-Chun
authors.initials: PC
authors.lastname: Tseng
authors.affiliation: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan;
authors.forename: Chia-Yuan
authors.initials: CY
authors.lastname: Hsieh
authors.affiliation: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; Department of Microbiology and Immunology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan 701, Taiwan; and Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan cflin2014@tmu.edu.tw.
authors.forename: Chiou-Feng
authors.initials: CF
authors.lastname: Lin
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology*; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D005753:Gastric Mucosa / Q000276:immunology / Q000382:microbiology; D016481:Helicobacter Infections / Q000276:immunology*; D016480:Helicobacter pylori / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000382:microbiology; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D020298:U937 Cells
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C080866:cagA protein, Helicobacter pylori; D007371:Interferon-gamma; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11