Abstract
Helicobacter pylori persistently colonizes the human stomach, and is associated with inflammation-induced gastric cancer. Bacterial crosstalk with the host immune system produces various inflammatory mediators and subsequent reactions in the host, but not bacterial clearance. Interleukin-1β (IL-1β) is implicated in gastric cancer development and certain gene polymorphisms play a role in this scenario. Mature IL-1β production depends on inflammasome activation, and the NLRP3 inflammasome is a major driver in H. pylori-infected mice, while recent studies demonstrated the down-regulation of NLRP3 expression in human immune cells, indicating a differential NLRP3 regulation in human vs. mice. In addition to the formation of mature IL-1β or IL-18, inflammasome activation induces pyroptotic death in cells. We demonstrate that H. pylori infection indeed upregulated the expression of pro-IL-1β in human immune cells, but secreted only very low amounts of mature IL-1β. However, application of exogenous control activators such as Nigericin or ATP to infected cells readily induced NLRP3 inflammasome formation and secretion of high amounts of mature IL-1β. This suggests that chronic H. pylori infection in humans manipulates inflammasome activation and pyroptosis for bacterial persistence. This inflammasome deregulation during H. pylori infection, however, is prone to external stimulation by microbial, environmental or host molecules of inflammasome activators for the production of high amounts of mature IL-1β and signaling-mediated gastric tumorigenesis in humans.
Highlights
Helicobacter pylori infection in the global human population is a major health burden in many parts of the world
The expression of pro-IL-1β is a prerequisite for mature IL-1β production, and its secretion proceeds through activation of the inflammasome
THP1 monocytes infected with P12 wild-type and isogenic mutants in major virulence factors (∆cagL, ∆vacA, ∆flaA, ∆LPS, ∆cytotoxicity associated gene pathogenicity island (cagPAI)) secreted similar amounts of mature IL-1β even after 24 h (Figure 1B), which suggests that these factors are not involved in Cancers 2020, 12, x FOR PEER REVIEW
Summary
Helicobacter pylori infection in the global human population is a major health burden in many parts of the world. A meta-analysis of published data revealed that 44.3% to 60.3% of the global population harbors this bacterium in their stomach [2]. H. pylori colonization causes mild gastritis in every colonized individual, 10–20% of cases are associated with the development of peptic ulcers, 1–2% develop gastric cancer and. H. pylori is a bacterial carcinogen recognized by the World Health Organization (WHO) due to the association with gastric cancer and MALT lymphoma [5]. The burden of gastric cancer increases every year and 1,033,701 new Cancers 2020, 12, 803; doi:10.3390/cancers12040803 www.mdpi.com/journal/cancers
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