title: Novel epidermal growth factor receptor pathway mediates release of human β-defensin 3 from Helicobacter pylori-infected gastric epithelial cells.
abstract: Persistent Helicobacter pylori (H. pylori) infection in hostile gastric mucosa can result in gastric diseases. Helicobacter pylori induces to express antimicrobial peptides from gastric epithelial cells, especially human β-defensin 3 (hBD3), as an innate immune response, and this expression of hBD3 is mediated by epidermal growth factor receptor (EGFR) activation. In this study, we found that phosphorylation of a serine residue of EGFR via transforming growth factor β-activated kinase-1 (TAK1), and subsequent p38α activation is essential for H. pylori-induced hBD3 release from gastric epithelial cells. We showed that this pathway was dependent on H. pylori type IV secretion system and was independent of H. pylori-derived CagA or peptidoglycan. H. pylori infection induced phosphorylation of serine residue of EGFR, and this phosphorylation was followed by internalization of EGFR; consequently, hBD3 was released at an early phase of the infection. In the presence of TAK1 or p38α inhibitors, synthesis of hBD3 was completely inhibited. Similar results were observed in EGFR-, TAK1- or p38α-knockdown cells. However, NOD1 knockdown in gastric epithelial cells did not inhibit hBD3 induction. Our study has firstly demonstrated that this novel EGFR activating pathway functioned to induce hBD3 at an early phase of H. pylori infection.
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Jibran S
authors.initials: JS
authors.lastname: Muhammad
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan Department of Basic Medical Sciences, College of Medicine, King Saud bin Abdulaziz University of Health Sciences, Jeddah 21423, Kingdom of Saudi Arabia.
authors.forename: Syed F
authors.initials: SF
authors.lastname: Zaidi
authors.affiliation: Department of Cancer Cell Biology, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Cancer Cell Biology, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Sakurai
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan tsugi@med.u-toyama.ac.jp.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Sugiyama
mesh_terms: D000942:Antigens, Bacterial / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology* / Q000382:microbiology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005753:Gastric Mucosa / Q000276:immunology* / Q000382:microbiology; D016481:Helicobacter Infections / Q000276:immunology* / Q000382:microbiology; D016480:Helicobacter pylori / Q000378:metabolism*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein / Q000235:genetics; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D000069319:Type IV Secretion Systems / Q000378:metabolism; D023083:beta-Defensins / Q000096:biosynthesis / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D066246:ErbB Receptors; D020930:MAP Kinase Kinase Kinases; D048308:Mitogen-Activated Protein Kinase 14; D053474:Nod1 Signaling Adaptor Protein; D034741:RNA, Small Interfering; D000069319:Type IV Secretion Systems; D023083:beta-Defensins; D000099151:MAP Kinase Kinase Kinase 7; C422950:DEFB103A protein, human; C507873:Nod1 protein, mouse; C080866:cagA protein, Helicobacter pylori; C512478:EGFR protein, human
keywords: EGFR; Helicobacter pylori; TAK1; host immune response; human β-defensin-3; p38α