Withaferin A Inhibits Helicobacter pylori-induced Production of IL-1beta in Dendritic Cells by Regulating NF-kappaB and NLRP3 Inflammasome Activation.
- Author:
Jae Eun KIM
1
;
Jun Young LEE
;
Min Jung KANG
;
Yu Jin JEONG
;
Jin A CHOI
;
Sang Muk OH
;
Kyung Bok LEE
;
Jong Hwan PARK
Author Information
- Publication Type:Original Article
- Keywords: Dendritic cells; Helicobacter pylori; Interleukin 1beta; NLRP3 inflammasome; Withaferin A
- MeSH: Blotting, Western; Caspase 1; Dendritic Cells*; Down-Regulation; Gastritis; Gene Expression; Helicobacter pylori; Helicobacter*; Humans; Interleukin-1beta; Interleukin-6; Macrophages; NF-kappa B*; Peptic Ulcer; Phosphorylation; Stomach Neoplasms; Withania
- From:Immune Network 2015;15(6):269-277
- CountryRepublic of Korea
- Language:English
- Abstract: Helicobacter pylori infection is associated with chronic gastritis, peptic ulcer, and gastric cancer. There is evidence that IL-1beta is associated with the development of gastric cancer. Therefore, downregulation of H. pylori-mediated IL-1beta 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-1beta in murine bone marrow-derived dendritic cells (BMDCs) and the underlying cellular mechanism. Co-treatment with WA decreased IL-1beta production by H. pylori in BMDCs in a dose-dependent manner. H. pylori-induced gene expression of IL-1beta and NLRP3 (NOD-like receptor family, pyrin domain containing 3) were also suppressed by WA treatment. Moreover, IkappaB-alpha 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-1beta, as well as increased procaspase-1 and pro IL-1beta 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-1beta 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-1beta and caspase-1 by NLRP3 activators was also dose-dependently inhibited by WA. These findings suggest that WA can inhibit IL-1beta production by H. pylori in dendritic cells and can be used as a new preventive and therapeutic agent for gastric cancer.
