title: Lymphotoxin β receptor signalling executesHelicobacter pylori-driven gastric inflammation in a T4SS-dependent manner.
abstract: Lymphotoxin β receptor (LTβR) signalling has been implicated in inflammation-associated tumour development in different tissues. We have analysed the role of LTβR and alternative NF-κB signalling inHelicobacter pylori-mediated gastric inflammation and pathology.
  
  
  
  We analysed several ligands and receptors of the alternative NF-κB pathway, RelB, p52 nuclear translocation and target genes in tissue samples ofH. pylori-infected patients with different degrees of gastritis or early gastric tumours by in situ hybridisation, immunohistochemistry, Western blot and real-time PCR analyses. Molecular mechanisms involved in LTβR activation byH. pyloriwere assessed in vitro using human gastric cancer cell lines and distinctH. pyloriisolates. The effects of blocking or agonistically activating LTβR on gastric pathology during challenge with a human pathogenicH. pyloristrain were studied in a mouse model.
  
  
  
  Among the tested candidates, LT was significantly increased and activated alternative NF-κB signalling was observed in the gastric mucosa ofH. pylori-infected patients.H. pyloriinduced LTβR-ligand expression in a type IV secretion system-dependent but CagA-independent manner, resulting in activation of the alternative NF-κB pathway, which was further enhanced by blocking canonical NF-κB during infection. Blocking LTβR signalling in vivo suppressedH. pylori-driven gastritis, whereas LTβR activation in gastric epithelial cells of infected mice induced a broadened pro-inflammatory chemokine milieu, resulting in exacerbated pathology.
  
  
  
  LTβR-triggered activation of alternative NF-κB signalling in gastric epithelial cells executesH. pylori-induced chronic gastritis, representing a novel target to restrict gastric inflammation and pathology elicited byH. pylori, while exclusively targeting canonical NF-κB may aggravate pathology by enhancing the alternative pathway.
authors.affiliation: Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich, Germany.|German Centre for Infection Research (DZIF), partner site Munich, Munich, Germany.
authors.forename: Raquel
authors.initials: R
authors.lastname: Mejías-Luque
authors.affiliation: Institut für Virologie, Technische Universität München, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Zöller
authors.affiliation: Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Anderl
authors.affiliation: Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Loew-Gil
authors.affiliation: Institut für Pathologie, Klinikum Bayreuth, Bayreuth, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Vieth
authors.affiliation: Immunology Screen, German Mouse Clinic, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Thure
authors.initials: T
authors.lastname: Adler
authors.affiliation: Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland.
authors.forename: Daniela B
authors.initials: DB
authors.lastname: Engler
authors.affiliation: Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: Urban
authors.affiliation: Department of Immunobiology, Biogen Idec, Cambridge, Massachusetts, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Browning
authors.affiliation: Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland.
authors.forename: Anne
authors.initials: A
authors.lastname: Müller
authors.affiliation: Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich, Germany.|German Centre for Infection Research (DZIF), partner site Munich, Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Gerhard
authors.affiliation: Institut für Virologie, Technische Universität München, Helmholtz Zentrum München, Neuherberg, Germany.|Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000378:metabolism; D054418:Chemokine CCL20 / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D005756:Gastritis / Q000378:metabolism* / Q000382:microbiology; D016481:Helicobacter Infections / Q000150:complications / Q000378:metabolism*; D016480:Helicobacter pylori; D006801:Humans; D053259:Lymphotoxin beta Receptor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D012333:RNA, Messenger; D015398:Signal Transduction; D051841:Transcription Factor RelB / Q000378:metabolism; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000069319:Type IV Secretion Systems / Q000378:metabolism*
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D018932:Chemokine CCL2; D054418:Chemokine CCL20; D054357:Chemokine CXCL10; D018925:Chemokines; D053259:Lymphotoxin beta Receptor; D016328:NF-kappa B; D012333:RNA, Messenger; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha; D000069319:Type IV Secretion Systems; C080866:cagA protein, Helicobacter pylori; D051841:Transcription Factor RelB
keywords: EPITHELIAL CELLS; HELICOBACTER PYLORI - GASTRITIS; HELICOBACTER PYLORI - PATHOGENESIS