title: Caspase-1 has both proinflammatory and regulatory properties in Helicobacter infections, which are differentially mediated by its substrates IL-1β and IL-18.
abstract: The proinflammatory cysteine protease caspase-1 is autocatalytically activated upon cytosolic sensing of a variety of pathogen-associated molecular patterns by Nod-like receptors. Active caspase-1 processes pro-IL-1β and pro-IL-18 to generate the bioactive cytokines and to initiate pathogen-specific immune responses. Little information is available on caspase-1 and inflammasome activation during infection with the gastric bacterial pathogen Helicobacter pylori. In this study, we addressed a possible role for caspase-1 and its cytokine substrates in the spontaneous and vaccine-induced control of Helicobacter infection, as well as the development of gastritis and gastric cancer precursor lesions, using a variety of experimental infection, vaccine-induced protection, and gastric disease models. We show that caspase-1 is activated and IL-1β and IL-18 are processed in vitro and in vivo as a consequence of Helicobacter infection. Caspase-1 activation and IL-1 signaling are absolutely required for the efficient control of Helicobacter infection in vaccinated mice. IL-1R(-/-) mice fail to develop protective immunity but are protected against Helicobacter-associated gastritis and gastric preneoplasia as a result of their inability to generate Helicobacter-specific Th1 and Th17 responses. In contrast, IL-18 is dispensable for vaccine-induced protective immunity but essential for preventing excessive T cell-driven immunopathology. IL-18(-/-) animals develop strongly accelerated pathology that is accompanied by unrestricted Th17 responses. In conclusion, we show in this study that the processing and release of a regulatory caspase-1 substrate, IL-18, counteracts the proinflammatory activities of another caspase-1 substrate, IL-1β, thereby balancing control of the infection with the prevention of excessive gastric immunopathology.
authors.affiliation: Institute of Molecular Cancer Research, University of Zürich, 8057 Zürich, Switzerland.
authors.forename: Iris
authors.initials: I
authors.lastname: Hitzler
authors.forename: Ayca
authors.initials: A
authors.lastname: Sayi
authors.forename: Esther
authors.initials: E
authors.lastname: Kohler
authors.forename: Daniela B
authors.initials: DB
authors.lastname: Engler
authors.forename: Katrin N
authors.initials: KN
authors.lastname: Koch
authors.forename: Wolf-Dietrich
authors.initials: WD
authors.lastname: Hardt
authors.forename: Anne
authors.initials: A
authors.lastname: Müller
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects; D000818:Animals; D001428:Bacterial Vaccines; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D005756:Gastritis / Q000209:etiology / Q000276:immunology* / Q000517:prevention & control; D005786:Gene Expression Regulation; D016481:Helicobacter Infections / Q000150:complications / Q000276:immunology* / Q000382:microbiology; D016480:Helicobacter pylori / Q000276:immunology; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013270:Stomach / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D013274:Stomach Neoplasms / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D014611:Vaccination
chemical_list: D001428:Bacterial Vaccines; D020382:Interleukin-18; D053583:Interleukin-1beta; D017472:Receptors, Interleukin-1; D020170:Caspase 1