Department of Nutrition, China Medical University, Taichung, Taiwan.
Department of Nutrition, China Medical University, Taichung, Taiwan; Department of Food Nutrition and Health Biotechnology, Asia University, Taichung, Taiwan.
Toxicol Appl Pharmacol. 2021 Jan 1;410:115341. doi: 10.1016/j.taap.2020.115341. Epub 2020 Nov 24.
Andrographolide (AND) is the major diterpenoid in A. paniculata with wide clinical application and has been shown to be a potent anti-inflammatory agent. Gout is the leading inflammatory disease of the joints, and the deposition of urate in the articular cavity attracts immune cells that release inflammatory cytokines. Monosodium urate (MSU) is known to be one of the activators of the NLRP3 (NLR family pyrin domain containing 3) inflammasome. After activation, the NLRP3 inflammasome releases interleukin-1β (IL-1β), which causes the development of many inflammatory diseases. The aim of the present study was to investigate whether AND attenuates the release of IL-1β mediated by the NLRP3 inflammasome. The effects of AND were studied in bone marrow-derived macrophages (BMDMs) treated with lipopolysaccharide (LPS) and MSU and in mice with MSU-induced joint inflammation. AND suppressed MSU phagocytosis dose-dependently and markedly inhibited LPS- and MSU-induced IL-1β release in BMDMs. Moreover, AND pretreatment inhibited the LPS-induced NLRP3 inflammasome priming stage by inhibiting the IKK/NFκB signaling pathway, which resulted in decreased protein expression of NLRP3 and proIL-1β. AND induced HO-1 protein expression in a dose-dependent manner and attenuated MSU-induced ROS generation. Silencing HO-1 mitigated AND inhibition of LPS/MSU-induced IL-1β release in J774A.1 cells. In addition, AND decreased MSU-mediated ASC binding to NLRP3. Oral administration of AND attenuated MSU-induced monocyte infiltration in mouse knee joints. These results suggest that the working mechanisms by which AND down-regulates MSU-induced joint inflammation might be via HO-1 induction and attenuation of ROS-mediated NLRP3 inflammasome assembly and subsequent IL-1β release.
穿心莲内酯（AND）是穿心莲中的主要二萜类化合物，具有广泛的临床应用，已被证明是一种有效的抗炎剂。痛风是关节的主要炎症性疾病，尿酸盐在关节腔内的沉积会吸引免疫细胞释放炎症细胞因子。单钠尿酸盐（MSU）已知是 NLRP3（NLR 家族包含 pyrin 结构域 3）炎性小体的激活剂之一。激活后，NLRP3 炎性小体释放白细胞介素-1β（IL-1β），导致许多炎症性疾病的发展。本研究旨在探讨 AND 是否能减轻 NLRP3 炎性小体介导的 IL-1β释放。研究了 AND 在骨髓来源的巨噬细胞（BMDM）中用脂多糖（LPS）和 MSU 处理以及在 MSU 诱导的关节炎症小鼠中的作用。AND 呈剂量依赖性抑制 MSU 吞噬作用，并显著抑制 BMDM 中 LPS 和 MSU 诱导的 IL-1β释放。此外，AND 通过抑制 IKK/NFκB 信号通路抑制 LPS 诱导的 NLRP3 炎性小体启动阶段，从而减少 NLRP3 和 proIL-1β的蛋白表达。AND 呈剂量依赖性诱导 HO-1 蛋白表达，并减轻 MSU 诱导的 ROS 生成。在 J774A.1 细胞中，沉默 HO-1 减轻了 AND 对 LPS/MSU 诱导的 IL-1β释放的抑制作用。此外，AND 减少了 MSU 介导的 ASC 与 NLRP3 的结合。AND 口服给药可减轻 MSU 诱导的小鼠膝关节单核细胞浸润。这些结果表明，AND 下调 MSU 诱导的关节炎症的作用机制可能是通过 HO-1 诱导和抑制 ROS 介导的 NLRP3 炎性小体组装和随后的 IL-1β释放。
