Jiayi Lin, Yaqin Zhang, Meihua Wang, Yang Zhang, Pin Li, Yingping Cao, Xuwei Yang
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Animal models of lupus were induced with pristane, whereas SC mice were treated with normal saline. From the 22<sup>nd</sup> week after induction, each group was given the aforementioned corresponding intervention for 11 weeks. The following variables were tested: serum concentrations of anti-double-stranded deoxyribonucleic acid (anti-dsDNA), interleukin 6 (IL-6), and interferon gamma (IFN-γ); number of regulatory T (Treg) cells; messenger ribonucleic acid levels of forkhead box P3 and 12 related genes downstream of JAK-STAT pathway; and renal impairment.</p><p><strong>Results: </strong>Red swollen joints and proteinuria were first observed in PC after the 12<sup>th</sup> week. After treatment, T, MP, and T+MP showed relieved red swollen joints and splenomegaly, as well as decreased urine protein, anti-dsDNA, IL-6, IFN-γ, Treg cells, pathological scores, and hyperplasia of mesangial matrix in glomeruli compared with PC. The IFN regulatory factor 7 level was higher in T+MP (p0.05) and MP (p>0.05) than in PC after treatment. The expression of suppressor of cytokine signaling (SOCS) 1 was lower in T (p>0.05), T+MP (p0.05) than in PC. The SOCS3 level was higher in T (p>0.05) and T+MP (p0.05) than in PC.</p><p><strong>Conclusion: </strong>Tofacitinib can ameliorate glomerulonephritis and arthritis in a pristane-induced murine model of lupus. 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Fifty-seven female BALB/c mice (aging 8 to 10 weeks old; weighing 18 to 20 g) were assigned to a saline control (SC) group and a pristane-induced lupus group. The latter included four groups, namely, pristane control (PC), tofacitinib (T), methylprednisolone (MP), and tofacitinib plus methylprednisolone (T+MP). Animal models of lupus were induced with pristane, whereas SC mice were treated with normal saline. From the 22<sup>nd</sup> week after induction, each group was given the aforementioned corresponding intervention for 11 weeks. The following variables were tested: serum concentrations of anti-double-stranded deoxyribonucleic acid (anti-dsDNA), interleukin 6 (IL-6), and interferon gamma (IFN-γ); number of regulatory T (Treg) cells; messenger ribonucleic acid levels of forkhead box P3 and 12 related genes downstream of JAK-STAT pathway; and renal impairment.</p><p><strong>Results: </strong>Red swollen joints and proteinuria were first observed in PC after the 12<sup>th</sup> week. After treatment, T, MP, and T+MP showed relieved red swollen joints and splenomegaly, as well as decreased urine protein, anti-dsDNA, IL-6, IFN-γ, Treg cells, pathological scores, and hyperplasia of mesangial matrix in glomeruli compared with PC. The IFN regulatory factor 7 level was higher in T+MP (p0.05) and MP (p>0.05) than in PC after treatment. The expression of suppressor of cytokine signaling (SOCS) 1 was lower in T (p>0.05), T+MP (p0.05) than in PC. 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引用次数: 1
摘要
目的:研究Janus kinase (JAK) 1/JAK3抑制剂tofacitinib治疗小鼠狼疮的疗效，并探索JAK-signal transducer and activator of transcription (STAT)信号通路下游的12个相关基因，寻找其作用机制。材料与方法:本研究于2017年7月至2020年1月进行。雌性BALB/c小鼠57只(8 ~ 10周龄;体重18 ~ 20 g)，分为生理盐水对照组(SC)和前列腺素诱导狼疮组。后者包括4组，即普里斯坦酮对照(PC)、托法替尼(T)、甲基强的松龙(MP)和托法替尼加甲基强的松龙(T+MP)。用普利斯坦诱导狼疮动物模型，用生理盐水处理SC小鼠。自诱导后第22周起，各组给予上述相应干预11周。检测以下变量:血清抗双链脱氧核糖核酸(anti-dsDNA)、白细胞介素6 (IL-6)、干扰素γ (IFN-γ)浓度;调节性T (Treg)细胞数量;叉头盒P3及JAK-STAT通路下游12个相关基因的信使核糖核酸水平;还有肾脏损伤。结果:PC术后12周首次出现关节红肿、蛋白尿。治疗后，与PC相比，T、MP、T+MP均表现为关节红肿、脾肿大减轻，尿蛋白、抗dsdna、IL-6、IFN-γ、Treg细胞、病理评分降低，肾小球系膜基质增生。治疗后，T+MP组和MP组IFN调节因子7水平均高于PC组(p>0.05)。细胞因子信号抑制因子(SOCS) 1在T、T+MP组的表达均低于PC组(p>0.05)。T组和T+MP组SOCS3水平均高于PC组(p>0.05)。结论:托法替尼可改善前列腺素诱导的狼疮模型小鼠肾小球肾炎和关节炎。SOCS3基因可能参与托法替尼的治疗机制。
Therapeutic Effects of Tofacitinib on Pristane-Induced Murine Lupus.
Objectives: This study aims to investigate the effectiveness of tofacitinib, a Janus kinase (JAK) 1/JAK3 inhibitor, in treating murine lupus, and also explore 12 related genes downstream of JAK-signal transducer and activator of transcription (STAT) signaling pathways to find the underlying mechanism.
Materials and methods: This study was conducted between July 2017 and January 2020. Fifty-seven female BALB/c mice (aging 8 to 10 weeks old; weighing 18 to 20 g) were assigned to a saline control (SC) group and a pristane-induced lupus group. The latter included four groups, namely, pristane control (PC), tofacitinib (T), methylprednisolone (MP), and tofacitinib plus methylprednisolone (T+MP). Animal models of lupus were induced with pristane, whereas SC mice were treated with normal saline. From the 22nd week after induction, each group was given the aforementioned corresponding intervention for 11 weeks. The following variables were tested: serum concentrations of anti-double-stranded deoxyribonucleic acid (anti-dsDNA), interleukin 6 (IL-6), and interferon gamma (IFN-γ); number of regulatory T (Treg) cells; messenger ribonucleic acid levels of forkhead box P3 and 12 related genes downstream of JAK-STAT pathway; and renal impairment.
Results: Red swollen joints and proteinuria were first observed in PC after the 12th week. After treatment, T, MP, and T+MP showed relieved red swollen joints and splenomegaly, as well as decreased urine protein, anti-dsDNA, IL-6, IFN-γ, Treg cells, pathological scores, and hyperplasia of mesangial matrix in glomeruli compared with PC. The IFN regulatory factor 7 level was higher in T+MP (p0.05) and MP (p>0.05) than in PC after treatment. The expression of suppressor of cytokine signaling (SOCS) 1 was lower in T (p>0.05), T+MP (p0.05) than in PC. The SOCS3 level was higher in T (p>0.05) and T+MP (p0.05) than in PC.
Conclusion: Tofacitinib can ameliorate glomerulonephritis and arthritis in a pristane-induced murine model of lupus. SOCS3 gene may be involved in the therapeutic mechanism of tofacitinib.
期刊介绍：
The Archives of Rheumatology is an official journal of the Turkish League Against Rheumatism (TLAR) and is published quarterly in March, June, September, and December. It publishes original work on all aspects of rheumatology and disorders of the musculoskeletal system. The priority of the Archives of Rheumatology is to publish high-quality original research articles, especially in inflammatory rheumatic disorders. In addition to research articles, brief reports, reviews, editorials, letters to the editor can also be published. It is an independent peer-reviewed international journal printed in English. Manuscripts are refereed by a "double-blind peer-reviewed" process for both referees and authors.
Editorial Board of the Archives of Rheumatology works under the principles of The World Association of Medical Editors (WAME), the International Council of Medical Journal Editors (ICMJE), and Committee on Publication Ethics (COPE).
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