title: The anti-tumorigenic mushroom Agaricus blazei Murill enhances IL-1β production and activates the NLRP3 inflammasome in human macrophages.
abstract: Agaricus blazei Murill (AbM) has been reported to possess immune activity against tumors and infections through stimulation of mononuclear phagocytes. Recently, AbM extract was shown to induce the production of the pro-inflammatory cytokine, interleukin-1β (IL-1β), in human monocytes. IL-1β is a key pro-inflammatory cytokine produced by activated macrophages and monocytes and its secretion is strictly controlled by the inflammasome. The purpose of this study is to investigate the effect of AbM water extracts on the regulation of IL-1β production and activation of the NLRP3 inflammasome in human THP-1 macrophages. The NLRP3 inflammasome consists of an NLRP3 receptor, an adaptor protein called ASC, and the inflammatory protease, caspase-1. Typically, stimulation of immune cells with microbial products results in production of pro-IL-1β, but a second stress-related signal activates the inflammasome and caspase-1, leading to processing and secretion of IL-1β. Our results show that AbM enhances transcription of IL-1β and triggers NLRP3 inflammasome-mediated IL-1β secretion in human THP-1 macrophages. AbM-mediated IL-1β secretion was markedly reduced in macrophages deficient in NLRP3 and ASC, demonstrating that the NLRP3 inflammasome is essential for AbM-induced IL-1β secretion. In addition, caspase-1 was activated and involved in proteolytic cleavage and secretion of IL-1β in AbM-treated macrophages. AbM-mediated IL-1β secretion also decreased in cells treated with cathepsin B inhibitor, suggesting that AbM can induce the release of cathepsin B. Furthermore, our data show that AbM-induced inflammasome activation requires the release of ATP, binding of extracellular ATP to the purinergic receptor P2X(7), the generation of reactive oxygen species, and efflux of potassium. Taken together, these findings reveal that AbM activates the NLRP3 inflammasome via multiple mechanisms, resulting in the secretion of IL-1β.
authors: Center for Molecular and Clinical Immunology, Chang Gung University, Taoyuan, Taiwan, Republic of China.
authors: Tsung-Teng
authors: TT
authors: Huang
authors: David M
authors: DM
authors: Ojcius
authors: John D
authors: JD
authors: Young
authors: Yi-Hui
authors: YH
authors: Wu
authors: Yun-Fei
authors: YF
authors: Ko
authors: Tsui-Yin
authors: TY
authors: Wong
authors: Cheng-Yeu
authors: CY
authors: Wu
authors: Chia-Chen
authors: CC
authors: Lu
authors: Hsin-Chih
authors: HC
authors: Lai
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000364:Agaricus / Q000737:chemistry*; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010936:Plant Extracts / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D010936:Plant Extracts; D017382:Reactive Oxygen Species; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate; D002401:Cathepsin B; D020170:Caspase 1; D011188:Potassium