Increased Notch pathway activation in Behçet's disease.
Increased Notch pathway activation in Behçet's disease.
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DOI：
10.1093/rheumatology/ket438
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发表时间：
2014-05
期刊：
影响因子：
5.5
通讯作者：
Jian-Yan Qi;Yan Yang;Shengping Hou;yanbin qiao;Qian Wang;Hongsong Yu;Qi Zhang;T. Cai;A. Kijlstra;Peizeng Yang
中科院分区：
文献类型：
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作者：
Jian-Yan Qi;Yan Yang;Shengping Hou;yanbin qiao;Qian Wang;Hongsong Yu;Qi Zhang;T. Cai;A. Kijlstra;Peizeng Yang
目的白塞病（BD）是一种病因不明的难治性炎症性疾病。由于Notch途径在免疫反应中起着关键作用，因此本研究旨在研究该途径在BD中的作用。方法采用实时荧光定量PCR、流式细胞术和ELISA法检测Hes-1、Notch 1-4、Jagged-1、DLL-1和DLL-4的表达、IFN-γ和IL-17表达的Th细胞频率、Notch胞内结构域（NICD）、信号转导和转录激活因子3（STAT 3）的磷酸化以及IFN-γ和IL-17的产生。使用γ-分泌酶抑制剂N-[N-（3，5-二氟苯乙酰基）-1-丙氨酰基]-S-苯基甘氨酸叔丁酯（DAPT）进行Notch阻断。使用miR-23 b模拟物和抑制剂转染来检查miR-23 b对Notch途径活化的影响。结果活动性BD患者Notch通路活化增强，Th 17应答增强。Notch阻断优先抑制Th 17应答。Notch阻断对Th 17应答的影响与较低水平的STAT 3磷酸化相关。活动性BD患者的CD 4（+）T细胞中miR-23 b显著降低。用miR-23 b转染的CD 4（+）T细胞显示NICD表达降低，IL-17和IFN-γ表达T细胞的频率降低。结论Notch信号通路的激活可能参与了BD的发病机制。miR-23 b的表达减少可能参与BD中Notch通路的激活。Notch通路的调控可能为BD提供新的治疗方法。
OBJECTIVE Behçet's disease (BD) is a refractory inflammatory disorder with unknown causes. Since the Notch pathway is critically involved in the immune response, the present study was undertaken to investigate the role of this pathway in BD. METHODS Hes-1, Notch 1-4, Jagged-1, DLL-1 and DLL-4 expression, frequency of IFN-γ and IL-17 expressing Th cells, Notch intracellular domain (NICD), phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the production of IFN-γ and IL-17 were examined by real-time PCR, flow cytometry and ELISA. Notch blockade was performed using the γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine t-butyl ester (DAPT). Transfection with miR-23b mimics and inhibitor was used to examine the effect of miR-23b on Notch pathway activation. RESULTS Active BD patients showed an increased activation of the Notch pathway in association with a higher Th17 response. Notch blockade preferentially inhibited Th17 responses. The effect of Notch blockade on the Th17 response was associated with a lower level of STAT3 phosphorylation. miR-23b was significantly decreased in CD4(+) T cells from active BD patients. CD4(+) T cells transfected with miR-23b showed a reduced expression of NICD and a reduced frequency of IL-17- and IFN-γ-expressing T cells. CONCLUSION The present study suggests that an increased activation of the Notch pathway may contribute to the pathogenesis of BD. Decreased expression of miR-23b may be involved in activation of the Notch pathway in BD. Manipulation of the Notch pathway may offer a novel therapeutic approach for BD.