title: Withaferin A Inhibits Helicobacter pylori-induced Production of IL-1β in Dendritic Cells by Regulating NF-κB and NLRP3 Inflammasome Activation.
abstract: Helicobacter pylori infection is associated with chronic gastritis, peptic ulcer, and gastric cancer. There is evidence that IL-1β is associated with the development of gastric cancer. Therefore, downregulation of H. pylori-mediated IL-1β production may be a way to prevent gastric cancer. Withaferin A (WA), a withanolide purified from Withania somnifera, is known to exert anti-inflammatory and anti-tumor effects. In the present study, we explored the inhibitory activity of WA on H. pylori-induced production of IL-1β in murine bone marrow-derived dendritic cells (BMDCs) and the underlying cellular mechanism. Co-treatment with WA decreased IL-1β production by H. pylori in BMDCs in a dose-dependent manner. H. pylori-induced gene expression of IL-1β and NLRP3 (NOD-like receptor family, pyrin domain containing 3) were also suppressed by WA treatment. Moreover, IκB-α phosphorylation by H. pylori infection was suppressed by WA in BMDCs. Western blot analysis revealed that H. pylori induced cleavage of caspase-1 and IL-1β, as well as increased procaspase-1 and pro IL-1β protein levels, and that both were suppressed by co-treatment with WA. Finally, we determined whether WA can directly inhibit ac tivation of the NLRP3 inflammasome. NLRP3 activators induced IL-1β secretion in LPS-primed macrophages, which was inhibited by WA in a dose-dependent manner, whereas IL-6 production was not affected by WA. Moreover, cleavage of IL-1β and caspase-1 by NLRP3 activators was also dose-dependently inhibited by WA. These findings suggest that WA can inhibit IL-1β production by H. pylori in dendritic cells and can be used as a new preventive and therapeutic agent for gastric cancer.
authors.affiliation: Department of Biochemistry, College of Medicine, Konyang University, Daejeon 35365, Korea.
authors.forename: Jae-Eun
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Laboratory Animal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Korea.
authors.forename: Jun-Young
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Laboratory Animal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Korea.
authors.forename: Min-Jung
authors.initials: MJ
authors.lastname: Kang
authors.affiliation: Department of Biochemistry, College of Medicine, Konyang University, Daejeon 35365, Korea.
authors.forename: Yu-Jin
authors.initials: YJ
authors.lastname: Jeong
authors.affiliation: Department of Biochemistry, College of Medicine, Konyang University, Daejeon 35365, Korea.
authors.forename: Jin-A
authors.initials: JA
authors.lastname: Choi
authors.affiliation: Department of Biochemistry, College of Medicine, Konyang University, Daejeon 35365, Korea.
authors.forename: Sang-Muk
authors.initials: SM
authors.lastname: Oh
authors.affiliation: Department of Biochemistry, College of Medicine, Konyang University, Daejeon 35365, Korea.
authors.forename: Kyung-Bok
authors.initials: KB
authors.lastname: Lee
authors.affiliation: Laboratory Animal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Korea.
authors.forename: Jong-Hwan
authors.initials: JH
authors.lastname: Park
keywords: Dendritic cells; Helicobacter pylori; Interleukin 1β; NLRP3 inflammasome; Withaferin A