Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Interruption of Helicobacter pylori-Induced NLRP3 Inflammasome Activation by Chalcone Derivatives

  • Choi, Hye Ri (College of Pharmacy, Kangwon National University) ;
  • Lim, Hyun (College of Pharmacy, Kangwon National University) ;
  • Lee, Ju Hee (College of Pharmacy, Kangwon National University) ;
  • Park, Haeil (College of Pharmacy, Kangwon National University) ;
  • Kim, Hyun Pyo (College of Pharmacy, Kangwon National University)
  • Received : 2020.10.29
  • Accepted : 2021.01.20
  • Published : 2021.07.01
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Abstract

Helicobacter pylori causes chronic gastritis through cag pathogenicity island (cagPAI), vacuolating cytotoxin A (VacA), lipopolysaccharides (LPS), and flagellin as pathogen-related molecular patterns (PAMPs), which, in combination with the pattern recognition receptors (PRRs) of host cells promotes the expression and secretion of inflammation-causing cytokines and activates innate immune responses such as inflammasomes. To identify useful compounds against H. pylori-associated gastric disorders, the effect of chalcone derivatives to activate the nucleotide-binding oligomerization domain (NOD)-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome was examined in an H. pylori-infected human monocytic THP-1 cell line in this study. Among the five synthetic structurally-related chalcone derivatives examined, 2'-hydroxy-4',6'-dimethoxychalcone (8) and 2'-hydroxy-3,4,5-trimethoxychalcone (12) strongly blocked the NLRP3 inflammasome in H. pylori-infected THP-1 cells. At 10 μM, these compounds inhibited the production of active IL-1β, IL-18, and caspase-1, and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) oligomerization, but did not affect the expression levels of NLRP3, ASC, and pro-caspase-1. The interruption of NLRP3 inflammasome activation by these compounds was found to be mediated via the inhibition of the interleukin-1 receptor-associated kinase 4 (IRAK4)/IκBα/NF-κB signaling pathway. These compounds also inhibited caspase-4 production associated with non-canonical NLRP3 inflammasome activation. These results show for the first time that certain chalcones could interrupt the activation of the NLRP3 inflammasome in H. pylori-infected THP-1 cells. Therefore, these chalcones may be helpful in alleviating H. pylori-related inflammatory disorders including chronic gastritis.

Keywords

Acknowledgement

This study was financially supported by the National Research Foundation of Korea (NRF) by the Korea government (MSIT) (NRF-2019R1F1A1051567) and BK21-plus of Ministry of Education (Korea). The bioassay facility of New Drug Development Institute (KNU) was used.

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