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靶向细胞因子信号传导抑制因子1通路治疗系统性红斑狼疮的治疗潜力

Therapeutic Potential for Targeting the Suppressor of Cytokine Signalling-1 Pathway for the Treatment of SLE.

作者信息

Sukka-Ganesh B, Larkin J

机构信息

Department of Microbiology and Cell Science, University of Florida, Gainesville, FL, USA.

出版信息

Scand J Immunol. 2016 Nov;84(5):299-309. doi: 10.1111/sji.12475.

Abstract

Although the specific events dictating systemic lupus erythematosus (SLE) pathology remain unclear, abundant evidence indicates a critical role for dysregulated cytokine signalling in disease progression. Notably, the suppressor of cytokine signalling (SOCS) family of intracellular proteins, in particular the kinase inhibitory region (KIR) bearing SOCS1 and SOCS3, plays a critical role in regulating cytokine signalling. To assess a relationship between SOCS1/SOCS3 expression and SLE, the goals of this study were to (1) evaluate the time kinetics of SOCS1/SOCS3 message and protein expression based on SLE-associated stimulations, (2) compare levels of SOCS1 and SOCS3 present in SLE patients and healthy controls by message and protein, (3) relate SOCS1/SOCS3 expression to inflammatory markers in SLE patients and (4) correlate SOCS1/SOCS3 levels to current treatments. We found that SOCS1 and SOCS3 were most abundant in murine splenic samples at 48 h subsequent to stimulation by anti-CD3, LPS or interferon-gamma. In addition, significant reductions in SOCS1 and SOCS3 were present within PMBCs of SLE patients compared to controls by both mRNA and protein expression. We also found that decreased levels of SOCS1 in SLE patients were correlated with enhanced levels of inflammatory markers and upregulated expression of MHC class II. Finally, we show that patients receiving steroid treatment possessed higher levels SOCS1 compared to SLE patient counterparts and that steroid administration to human PBMCs upregulated SOCS1 message in a dose- and time-dependent manner. Together, these results suggest that therapeutic strategies focused on SOCS1 signalling may have efficacy in the treatment of SLE.

摘要

尽管决定系统性红斑狼疮(SLE)病理的具体事件仍不清楚,但大量证据表明细胞因子信号失调在疾病进展中起关键作用。值得注意的是,细胞内蛋白细胞因子信号抑制因子(SOCS)家族,特别是带有激酶抑制区域(KIR)的SOCS1和SOCS3,在调节细胞因子信号中起关键作用。为了评估SOCS1/SOCS3表达与SLE之间的关系,本研究的目标是:(1)基于与SLE相关的刺激评估SOCS1/SOCS3信息和蛋白表达的时间动力学;(2)通过信息和蛋白比较SLE患者和健康对照中SOCS1和SOCS3的水平;(3)将SLE患者中SOCS1/SOCS3表达与炎症标志物相关联;(4)将SOCS1/SOCS3水平与当前治疗相关联。我们发现,在抗CD3、LPS或干扰素-γ刺激后48小时,SOCS1和SOCS3在小鼠脾脏样本中最为丰富。此外,与对照组相比,SLE患者外周血单个核细胞(PBMC)中的SOCS1和SOCS3在mRNA和蛋白表达水平上均显著降低。我们还发现,SLE患者中SOCS1水平降低与炎症标志物水平升高和MHC II类表达上调相关。最后,我们表明,接受类固醇治疗的患者与未接受治疗的SLE患者相比,SOCS1水平更高,并且向人PBMC中给予类固醇以剂量和时间依赖性方式上调SOCS1信息。总之,这些结果表明,针对SOCS1信号的治疗策略可能对SLE治疗有效。

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