Procyanidin B2 inhibits inflammasome-mediated IL-1β production in lipopolysaccharide-stimulated macrophages.

Macrophage stimulation with bacterial LPS triggers inflammasome activation, resulting in pro-inflammatory IL-1β cytokine maturation and secretion. IL-1β underlies the pathologies of many diseases, including type-2 diabetes. Thus, the modulation of the inflammatory response through bioactive food compounds, such as procyanidins, is a powerful tool to promote homeostasis. To determine the role of procyanidin B2 in inflammasome activation, LPS-primed THP-1-macrophages were supplemented with or without procyanidin B2 . Western blot analysis of COX2 , iNOS, p65, NLRP3 and IL-1β was performed followed by p65 supershift assay, in vivo caspase-1 activation assay and NO, IL-1β and IL-6 determination. Procyanidin B2 mediated inhibition of inflammasome activation includes the inactivation of the NF-κB signalling pathway, the first stage required for the transcription of inflammasome precursors, through the inhibition of p65 nuclear expression and DNA binding, resulting in the transcriptional repression of target genes, such as COX2 , iNOS and production of IL-6 and NO. Furthermore, procyanidin B2 decreases NLRP3 and pro-IL-1β cytoplasmic pools, limiting components of inflammasome activation and impeding inflammasome assembly and caspase-1 activation, and finally secretion of active IL-1β. This study provides the first evidence that procyanidin B2 inhibits inflammasome activation and IL-1β secretion during LPS-induced acute inflammation in human macrophages.

Martinez-Micaelo N ，González-Abuín N ，Pinent M ，Ardévol A ，Blay M ... -  《-》

Aloe vera downregulates LPS-induced inflammatory cytokine production and expression of NLRP3 inflammasome in human macrophages.

Budai MM ，Varga A ，Milesz S ，Tőzsér J ，Benkő S ... -  《-》

Procyanidin B2 inhibits NLRP3 inflammasome activation in human vascular endothelial cells.

Procyanidins are the flavanols from polyphenols commonly found in fruits and red wine. Recent studies have shown that procyanidins possess potential anti-inflammatory activities. However, underlying mechanisms remain to be understood. Inflammasomes are multi-protein complexes composed of pro-caspase and pattern recognition receptors (PRRs) such as NOD-like receptor family, pyrin domain containing 3 (NLRP3). Since aberrant activation of NLRP3 inflammasome is implicated in the pathogeneses of pro-inflammatory diseases such as diabetes, atherosclerosis and arthritis, we aimed to investigate whether procyanidin B2 (PCB2), the most widely distributed natural procyanidins, inhibits the activation of NLRP3 inflammasome in endothelial cells (ECs). We found that, in human umbilical vein ECs (HUVECs), PCB2 significantly suppressed the activation of NLRP3 inflammasome and inhibited subsequent caspase-1 activation and interleukin (IL)-1β secretion in response to lipopolysaccharides (LPS). PCB2 negatively regulated the gene expression of NLRP3. In addition, PCB2 attenuated LPS-induced production of reactive oxygen species (ROS) and the transcriptional activity of activator protein-1 (AP-1). In conclusion, we demonstrated for the first time that procyanidin B2 inhibits NLRP3 inflammasome activation via suppression of AP-1 pathway in ECs. These results suggest a new mechanism by which natural flavoids such as procyanidins exert their vascular protective effects.

Yang H ，Xiao L ，Yuan Y ，Luo X ，Jiang M ，Ni J ，Wang N ... -  《-》

Cyclooxygenase-2 regulates NLRP3 inflammasome-derived IL-1β production.

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.

Hua KF ，Chou JC ，Ka SM ，Tasi YL ，Chen A ，Wu SH ，Chiu HW ，Wong WT ，Wang YF ，Tsai CL ，Ho CL ，Lin CH ... -  《-》

Management of Gout-associated MSU crystals-induced NLRP3 inflammasome activation by procyanidin B2: targeting IL-1β and Cathepsin B in macrophages.

Qiao CY ，Li Y ，Shang Y ，Jiang M ，Liu J ，Zhan ZY ，Ye H ，Lin YC ，Jiao JY ，Sun RH ，Zhang ZH ，Piao MH ，Wu YL ，Nan JX ，Lian LH ... -  《-》