Abstract
Aims: In the NOD-like receptor (NLR) family, the pyrin domain containing 3 (NLRP3) inflammasome is closely related to the progression of atherosclerosis. This study aimed to assess the effects of curcumin on NLRP3 inflammasome in phorbol 12-myristate 13-acetate (PMA)-induced macrophages and explore its underlying mechanism.Methods: Human monocytic THP-1 cells were pretreated with curcumin for 1 h and subsequently induced with PMA for 48 h. Total protein was collected for Western blot analysis. Cytokine interleukin (IL)-1β release and nuclear factor kappa B (NF-κB) p65 translocation were detected by ELISA assay and cellular NF-κB translocation kit, respectively.Results: Curcumin significantly reduced the expression of NLRP3 and cleavage of caspase-1 and IL-1β secretion in PMA-induced macrophages. Moreover, Bay (a NF-κB inhibitor) treatment considerably suppressed the expression of NLRP3 inflammasome in PMA-induced THP-1 cells. Curcumin also markedly inhibited the upregulation of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), phosphorylation level of IκB-α, and activation of NF-κB in PMA-induced macrophages. In addition, purinergic 2X7 receptor (P2X7R) siRNA was administered, and it significantly decreased NLRP3 inflammasome expression in PMA-induced macrophages. Furthermore, curcumin reversed PMA-stimulated P2X7R activation, which further reduced the expression of NLRP3 and cleavage of caspase-1 and IL-1β secretion. Silencing of P2X7R using siRNA also suppressed the activation of NF-κB pathway in PMA-induced macrophages, but P2X7R-silenced cells did not significantly decrease the expression of TLR4 and MyD88.Conclusion: Curcumin inhibited NLRP3 inflammasome through suppressing TLR4/MyD88/NF-κB and P2X7R pathways in PMA-induced macrophages.
Highlights
Atherosclerosis is a chronic and progressive immunoinflammatory disease
Curcumin markedly inhibited the upregulation of tolllike receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), phosphorylation level of IκB-α, and activation of NF-κB in phorbol 12-myristate 13acetate (PMA)-induced macrophages
Curcumin reversed PMA-stimulated purinergic 2X7 receptor (P2X7R) activation, which further reduced the expression of NLRP3 and cleavage of caspase-1 and IL-1β secretion
Summary
Atherosclerosis is a chronic and progressive immunoinflammatory disease. Monocytes are one of major factors in the development of this disease. Focal recruitment of circulating monocytes is one of the earliest cellular responses, which underlie disease progression. Inflammatory factors, which are released by the newly differentiated macrophages, play key roles in the pathophysiology of atherosclerosis (Glass and Witztum, 2001; Libby, 2002; Hansson, 2005). For the NOD-like receptor (NLR) family, the pyrin domain containing 3 (NLRP3) inflammasome plays a crucial role in the inflammatory response (Schroder and Tschopp, 2010). NLRP3 inflammasome is a multiprotein complex that consists of NLRP3, an apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and caspase-1 (Latz et al, 2013). NLRP3 recruits its adaptor ASC and procaspase-1 to form an inflammasome complex; caspase-1 is activated, which causes the cleavage of the proforms of interleukin (IL)-1β and IL-18 to their mature forms (Martinon et al, 2009). IL1β is a fundamental pro-inflammatory cytokine in mediating atherosclerosis progression (Elhage et al, 1998; Duewell et al, 2010)
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