Withaferin A Inhibits Helicobacter Pylori-Induced Production Of Il-1 Beta In Dendritic Cells By Regulating Nf-Kappa B And Nlrp3 Inflammasome Activation

Helicobacter pylori infection is associated with chronic gastritis, peptic ulcer, and gastric cancer. There is evidence that IL-1 beta is associated with the development of gastric cancer. Therefore, downregulation of H. pylori-mediated IL-1 beta 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-1 beta in murine bone marrow-derived dendritic cells (BMDCs) and the underlying cellular mechanism. Co-treatment with WA decreased IL-1 beta production by H. pylori in BMDCs in a dose-dependent manner. H. pylori-induced gene expression of IL-1 beta and NLRP3 (NOD-like receptor family, pyrin domain containing 3) were also suppressed by WA treatment. Moreover, I kappa B-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-1 beta, as well as increased procaspase-1 and pro IL-1 beta protein levels, and that both were suppressed by co-treatment with WA. Finally, we determined whether WA can directly inhibit activation of the NLRP3 inflammasome. NLRP3 activators induced IL-1 beta 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-1 beta and caspase-1 by NLRP3 activators was also dose-dependently inhibited by WA. These findings suggest that WA can inhibit IL-1 beta production by H. pylori in dendritic cells and can be used as a new preventive and therapeutic agent for gastric cancer.