* Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
† Department of Medicine, Division of Allergy, Immunology and Rheumatology, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Keelung, Taiwan.
Am J Chin Med. 2019;47(1):135-151. doi: 10.1142/S0192415X19500071. Epub 2019 Jan 7.
Rhein, an anthraquinone drug, is a widely used traditional Chinese medicine. Rhein is a major bioactive metabolite of diacerein which has been approved for treating osteoarthritis with a good safety profile in humans. Gouty arthritis is an inflammatory disease characterized by urate crystal-induced NLRP3 inflammasome activation with up-regulated caspase-1 protease and IL-1 in macrophages. Inhibition of the NLRP3 inflammasome formation has been considered as a potential therapeutic avenue for treating or preventing many inflammatory diseases. This study aimed to evaluate the anti-inflammatory effects of rhein on gouty arthritis. Rhein within the physiological levels of humans showed no toxicity on the cell viability and differentiation, but significantly decreased the production of IL-1 , TNF- and caspase-1 protease in urate crystal-activated macrophages. Compared to medium controls, rhein at the therapeutic concentration (2.5 g/mL) effectively inhibited IL-1 production by 47% ( ). Rhein did not affect the mRNA levels of CASP1, NLRP3 and ASC, but suppressed the protein expression and enzyme activity of caspase-1. Immunofluorescence confocal microscopy further revealed that rhein suppressed the aggregation of ASC speck and inhibited the formation of NLRP3 inflammasome. Rhein of 5 g/mL significantly decreased the ASC speck to 36% ( ), and reduced the NLRP3 aggregates to 37.5% ( ). Our data demonstrate that rhein possesses pharmacological activity to suppress caspase-1 protease activity and IL-1 production by interfering with the formation of NLRP3 multiprotein complex. These results suggest that rhein has therapeutic potential for treating NLRP3 inflammasome-mediated diseases such as gouty arthritis.
大黄酸，蒽醌类药物，是一种广泛应用的中药。大黄酸是已被批准用于治疗骨关节炎的二乙酰氨己酸的主要生物活性代谢物，在人体中具有良好的安全性。痛风性关节炎是一种炎症性疾病，其特征是尿酸盐晶体诱导 NLRP3 炎性小体激活，导致巨噬细胞中 caspase-1 蛋白酶和白细胞介素-1 (IL-1β)上调。抑制 NLRP3 炎性小体的形成被认为是治疗或预防许多炎症性疾病的潜在治疗途径。本研究旨在评估大黄酸对痛风性关节炎的抗炎作用。在生理浓度范围内，大黄酸对细胞活力和分化没有毒性，但显著降低了尿酸盐晶体激活的巨噬细胞中白细胞介素-1β (IL-1β)、肿瘤坏死因子-α (TNF-α)和 caspase-1 蛋白酶的产生。与培养基对照相比，治疗浓度（2.5 g/mL）的大黄酸有效地抑制了 47%（ ）的 IL-1β产生。大黄酸不影响 CASP1、NLRP3 和 ASC 的 mRNA 水平，但抑制了 caspase-1 的蛋白表达和酶活性。免疫荧光共聚焦显微镜进一步显示，大黄酸抑制了 ASC 斑点的聚集，并抑制了 NLRP3 炎性小体的形成。大黄酸 5 g/mL 可使 ASC 斑点减少到 36%（ ），并使 NLRP3 聚集体减少到 37.5%（ ）。我们的数据表明，大黄酸具有药理学活性，可通过干扰 NLRP3 多蛋白复合物的形成来抑制 caspase-1 蛋白酶活性和 IL-1β的产生。这些结果表明，大黄酸具有治疗 NLRP3 炎性小体介导的疾病（如痛风性关节炎）的潜力。
