Caspase-1 Has Both Proinflammatory and Regulatory Properties in Helicobacter Infections, Which Are Differentially Mediated by Its Substrates IL-1 beta and IL-18

Hitzler I., Sayi A., Kohler E., Engler D. B. , Koch K. N. , HARDT W., ...More

JOURNAL OF IMMUNOLOGY, vol.188, no.8, pp.3594-3602, 2012 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Volume: 188 Issue: 8
  • Publication Date: 2012
  • Doi Number: 10.4049/jimmunol.1103212
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.3594-3602
  • Istanbul Technical University Affiliated: Yes


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-1 beta 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-1 beta 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-1 beta, thereby balancing control of the infection with the prevention of excessive gastric immunopathology. The Journal of Immunology, 2012, 188: 3594-3602.