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.

Innate and adaptive effects of inflammasomes on T cell responses

“…The use of Nlrc4-and Nlrp3-further suggested inflammasome relevance in inducing Th17 responses upon Legionella pneumophila and Schistosoma mansoni infection, respectively [44 ,45 ]. In contrast, caspase-1 ablation did not reduce IL-17 production in the context of Helicobacter pylori infection, while IL-18 deficiency promoted it, pinpointing the relevance of inflammasome substrates in modulating the adaptive immune response [41 ].…”

Cytokine Regulation of Ulcerogenesis in Gastroduodenal Mucosa

“…Инфекция H. pylori индуцирует повышенную выработку IL1β и IL18 как в эксперименталь ных, так и в естественных условиях [19,29]. По казано [35], что H. pylori влияет на уровни каспаз, необходимых для расщепления proIL1 и pro IL18 в активные белки.…”

“…В эксперименте у мышей, дефицитных по гену IL1β, отмечались неспособность к клеточному иммунному ответу на антигены H. pylori, отсутствие воспалительных и метапластических изменений СО. У животных с нокаутом гена IL18 наблюдался неконтроли руемый избыточный Th17иммунный ответ, спо собствующий прогрессированию патологическо го процесса [29].…”

The Role of Interleukin-1 and Associated Cytokines in Gastric Carcinogenesis

“…Установлено, что при инфицировании организма активируется сериновая протеаза -каспаза-1, необхо-димая для превращения неактивных белковых молекул про-ИЛ-1β и про-ИЛ-18 в активные цитокины, участву-ющие в формировании патоген-специфического иммун-ного ответа [24]. Существуют данные о том, что белок CagA H. pylori, обладающий наибольшей вирулентно-стью, может активировать NF-kВ, приводя к стиму-ляции провоспалительных сигналов и секреции ИЛ-1, -8, накоплению мутаций в гене-супрессоре опухоли p53 [19].…”