https://scholars.lib.ntu.edu.tw/handle/123456789/455884
標題: | Simvastatin inhibits cysteine-rich protein 61 expression in rheumatoid arthritis synovial fibroblasts through the regulation of sirtuin-1/FoxO3a signaling | 作者: | SANG-HENG KOK LI-DEH LIN Hou K.-L. Hong C.-Y. Chang C.-C. Hsiao M. JYH-HORNG WANG EDDIE HSIANG HUA LAI SZE-KWAN LIN |
公開日期: | 2013 | 卷: | 65 | 期: | 3 | 起(迄)頁: | 639-649 | 來源出版物: | Arthritis and Rheumatism | 摘要: | Objective To examine the role of sirtuin-1 (SIRT-1)/FoxO3a in the expression of cysteine-rich protein 61 (CYR-61) in rheumatoid arthritis synovial fibroblasts (RASFs) and the influence of simvastatin on this pathway, and to determine the relationship between disease progression and FoxO3a/CYR-61 signaling in synovial fibroblasts in vivo using a rat model of collagen-induced arthritis (CIA). Methods In RASFs, the expression of CYR-61 and SIRT-1, the localization of FoxO3a in the nucleus/cytoplasm, and the phosphorylation/ acetylation of FoxO3a were examined by Western blotting. Secretion of CCL20 was assessed by enzyme-linked immunosorbent assay. Promoter activity of the Cyr61 gene was evaluated by luciferase assay, with or without forced expression of FoxO3a and SIRT-1 by lentiviral transduction. FoxO3a-Cyr61 promoter interaction was examined by chromatin immunoprecipitation. In rats with CIA, the expression of CYR-61 and phosphorylated FoxO3a in synovial fibroblasts was examined by immunohistochemistry. Results In RASFs, simvastatin suppressed the tumor necrosis factor α (TNFα)-induced production of CYR-61 and CCL20. Nuclear levels of FoxO3a were decreased after TNFα stimulation of RASFs, and forced expression of FoxO3a reversed the inductive effects of TNFα on CYR-61. Simvastatin inhibited the nuclear export, phosphorylation, and acetylation of FoxO3a and maintained its binding to the Cyr61 promoter. Forced expression of SIRT-1 in RASFs led to decreased levels of CYR-61 and deacetylation of FoxO3a. Following treatment with simvastatin, the expression of SIRT-1 was up-regulated and SIRT-1/FoxO3a binding was enhanced in RASFs. In rats with CIA, intraarticular injection of simvastatin alleviated arthritis and suppressed CYR-61 expression and FoxO3a phosphorylation in synovial fibroblasts. Conclusion CYR-61 is important in the pathogenesis of RA, and SIRT-1/FoxO3a signaling is crucial to induction of CYR-61 in RASFs. Simvastatin plays a beneficial role in inflammatory arthritis through its up-regulation of SIRT-1/FoxO3a signaling in synovial fibroblasts. Continued study of the pathways linking sirtuins, FoxO proteins, and the inflammatory responses of RASFs may provide new insights into the pathophysiology of RA. ? 2013 by the American College of Rheumatology. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84874447190&doi=10.1002%2fart.37807&partnerID=40&md5=8e6e2bd5fd1afe3849f32a1576a08ad3 https://scholars.lib.ntu.edu.tw/handle/123456789/455884 |
ISSN: | 0004-3591 | DOI: | 10.1002/art.37807 | SDG/關鍵字: | cysteine rich protein 61; lentivirus vector; luciferase; macrophage inflammatory protein 3alpha; simvastatin; sirtuin 1; transcription factor FKHRL1; tumor necrosis factor alpha; acetylation; animal experiment; animal model; animal tissue; arthritis; article; cell nucleus; chromatin immunoprecipitation; controlled study; cytoplasm; deacetylation; disease course; enzyme assay; enzyme linked immunosorbent assay; fibroblast; gene activity; human; human cell; human tissue; immunohistochemistry; in vivo study; male; nonhuman; nuclear export signal; pathogenesis; pathophysiology; priority journal; promoter region; protein expression; protein function; protein localization; protein phosphorylation; protein secretion; rat; regulatory mechanism; rheumatoid arthritis; signal transduction; synoviocyte; upregulation; Western blotting; Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Cells, Cultured; Chemokine CCL20; Cysteine-Rich Protein 61; Disease Models, Animal; Fibroblasts; Forkhead Transcription Factors; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Rats; Rats, Sprague-Dawley; Signal Transduction; Simvastatin; Sirtuin 1; Synovial Membrane; Tumor Necrosis Factor-alpha |
顯示於: | 醫學系 |
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