title: Cyclooxygenase-2 regulates NLRP3 inflammasome-derived IL-1β production.
abstract: The NLR family, pyrin domain-containing 3 (NLRP3) inflammasome is a reactive oxygen species-sensitive multiprotein complex that regulates IL-1β maturation via caspase-1. It also plays an important role in the pathogenesis of inflammation-related disease. Cyclooxygenase-2 (COX-2) is induced by inflammatory stimuli and contributes to the pathogenesis of inflammation-related diseases. However, there is currently little known about the relationship between COX-2 and the NLRP3 inflammasome. Here, we describe a novel role for COX-2 in regulating the activation of the NLRP3 inflammasome. NLRP3 inflammasome-derived IL-1β secretion and pyroptosis in macrophages were reduced by pharmaceutical inhibition or genetic knockdown of COX-2. COX-2 catalyzes the synthesis of prostaglandin E2 and increases IL-1β secretion. Conversely, pharmaceutical inhibition or genetic knockdown of prostaglandin E2 receptor 3 reduced IL-1β secretion. The underlying mechanisms for the COX-2-mediated increase in NLRP3 inflammasome activation were determined to be the following: (1) enhancement of lipopolysaccharide-induced proIL-1β and NLRP3 expression by increasing NF-κB activation and (2) enhancement of the caspase-1 activation by increasing damaged mitochondria, mitochondrial reactive oxygen species production and release of mitochondrial DNA into cytosol. Furthermore, inhibition of COX-2 in mice in vivo with celecoxib reduced serum levels of IL-1β and caspase-1 activity in the spleen and liver in response to lipopolysaccharide (LPS) challenge. These findings provide new insights into how COX-2 regulates the activation of the NLRP3 inflammasome and suggest that it may be a new potential therapeutic target in NLRP3 inflammasome-related diseases.
authors.affiliation: Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan.
authors.forename: Kuo-Feng
authors.initials: KF
authors.lastname: Hua
authors.forename: Ju-Ching
authors.initials: JC
authors.lastname: Chou
authors.forename: Shuk-Man
authors.initials: SM
authors.lastname: Ka
authors.forename: Yu-Ling
authors.initials: YL
authors.lastname: Tasi
authors.forename: Ann
authors.initials: A
authors.lastname: Chen
authors.forename: Shih-Hsiung
authors.initials: SH
authors.lastname: Wu
authors.forename: Hsiao-Wen
authors.initials: HW
authors.lastname: Chiu
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Wong
authors.forename: Yih-Fuh
authors.initials: YF
authors.lastname: Wang
authors.forename: Change-Ling
authors.initials: CL
authors.lastname: Tsai
authors.forename: Chen-Lung
authors.initials: CL
authors.lastname: Ho
authors.forename: Cheng-Hsiu
authors.initials: CH
authors.lastname: Lin
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D053583:Interleukin-1beta / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D020170:Caspase 1