Kim Seong-Kyu, Choe Jung-Yoon, Kim Ji-Won, Park Ki-Yeun, Kim Boyoung
Division of Rheumatology, Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu 42472, Republic of Korea.
Arthritis and Autoimmunity Research Center, Catholic University of Daegu, Daegu 42472, Republic of Korea.
Pharmaceuticals (Basel). 2024 Jul 3;17(7):883. doi: 10.3390/ph17070883.
: The pleiotropic effect of hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) is responsible for potent defense against inflammatory response. This study evaluated the inhibitory effects of HMG-CoA reductase inhibitors on the monosodium urate (MSU)-induced inflammatory response through the regulation of interleukin-37 (IL-37) expression. : Serum was collected from patients with gout ( = 40) and from healthy controls ( = 30). The mRNA and protein expression of the target molecules IL-1β, IL-37, caspase-1, and Smad3 were measured in THP-1 macrophages stimulated with MSU, atorvastatin, or rosuvastatin using a real-time quantitative polymerase chain reaction and Western blot assay. Transfection with IL-1β or Smad3 siRNA in THP-1 macrophages was used to verify the pharmaceutical effect of statins in uric-acid-induced inflammation. : Serum IL-37 levels in gout patients were significantly higher than in controls ( < 0.001) and was associated with the serum uric acid level ( = 0.382, = 0.008). THP-1 cells stimulated with MSU markedly induced IL-37 mRNA expression and the transition of IL-37 from the cytoplasm to the nucleus. Recombinant IL-37 treatment dose-dependently inhibited activation of caspase-1 and IL-1β in MSU-induced inflammation. Atorvastatin and rosuvastatin attenuated caspase-1 activation and mature IL-1β expression but augmented translocation of IL-37 from the cytoplasm to the nucleus. Atorvastatin and rosuvastatin induced phosphorylation of Smad3 in THP-1 cells treated with MSU crystals. Statins potently attenuated translocation of IL-37 from the cytoplasm to the nucleus in THP-1 macrophages transfected with Smad3 siRNA compared to cells with negative control siRNA. : This study revealed that statins inhibit the MSU-induced inflammatory response through phosphorylated Smad3-mediated IL-37 expression in THP-1 macrophages.
羟甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂（他汀类药物）的多效性作用对炎症反应具有强大的防御作用。本研究通过调节白细胞介素-37（IL-37）的表达来评估HMG-CoA还原酶抑制剂对尿酸钠（MSU）诱导的炎症反应的抑制作用。：从痛风患者（n = 40）和健康对照者（n = 30）中采集血清。使用实时定量聚合酶链反应和蛋白质印迹分析，在经MSU、阿托伐他汀或瑞舒伐他汀刺激的THP-1巨噬细胞中测量靶分子IL-1β、IL-37、半胱天冬酶-1和Smad3的mRNA和蛋白质表达。在THP-1巨噬细胞中转染IL-1β或Smad3 siRNA，以验证他汀类药物在尿酸诱导的炎症中的药理作用。：痛风患者血清IL-37水平显著高于对照组（P < 0.001），且与血清尿酸水平相关（r = 0.382，P = 0.008）。用MSU刺激的THP-1细胞显著诱导IL-37 mRNA表达以及IL-37从细胞质向细胞核的转位。重组IL-37处理在MSU诱导的炎症中剂量依赖性地抑制半胱天冬酶-1和IL-1β的激活。阿托伐他汀和瑞舒伐他汀减弱了半胱天冬酶-1的激活和成熟IL-1β的表达，但增强了IL-37从细胞质向细胞核的转位。阿托伐他汀和瑞舒伐他汀在经MSU晶体处理的THP-1细胞中诱导Smad3的磷酸化。与用阴性对照siRNA转染的细胞相比，他汀类药物在转染Smad3 siRNA的THP-1巨噬细胞中显著减弱了IL-37从细胞质向细胞核的转位。：本研究表明，他汀类药物通过磷酸化Smad3介导的IL-37表达抑制THP-1巨噬细胞中MSU诱导的炎症反应。
