Induction of Notch signaling by tumor necrosis factor in rheumatoid synovial fibroblasts
Induction of Notch signaling by tumor necrosis factor in rheumatoid synovial fibroblasts
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DOI：
10.1038/sj.onc.1206965
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发表时间：
2003-10-30
期刊：
影响因子：
8
通讯作者：
Okamoto, T
中科院分区：
文献类型：
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作者：
Ando, K;Kanazawa, S;Okamoto, T
类风湿性关节炎（RA）是一种以滑膜细胞异常增殖为特征的进行性炎症反应。为了探讨类风湿性滑膜成纤维细胞（RSF）的特点，我们对RSF和正常滑膜组织进行了基因表达谱的比较分析。成纤维细胞（NSF）在肿瘤坏死因子（TNF）刺激。与NSF相比，作为RSF中TNF优先诱导的基因的初步筛选，我们采用了包含负责细胞生长、细胞命运决定和细胞侵袭性的基因的定义明确的cDNA阵列。使用实时RT-PCR确认差异表达的目的基因。我们发现TNF诱导RSF中Notch-1、Notch-4和Jagged-2的表达。这些蛋白在RA滑膜组织中均有表达。抗Notch-1和Notch-4抗体对RA滑膜细胞核显示强染色。TNF诱导RSF中Notch胞内结构域的核转位，表明Notch信号的激发。Notch-1、Notch-4和Jagged-2蛋白在小鼠胚胎滑膜中也有表达。因此，RSF可能重新获得了原始表型，解释了过度增殖和侵袭性，表现出肿瘤样表型。
Rheumatoid arthritis ( RA) is characterized by progressive inflammation associated with abberrant proliferation of synoviocytes. In order to explore the characteristics of rheumatoid synovial fibroblasts (RSF), we performed the comparative gene expression profile analysis between RSF and normal synovial. broblasts (NSF) upon tumor necrosis factor (TNF) stimulation. As an initial screening for the genes preferentially induced by TNF in RSF compared with NSF, we have adopted a cDNA array containing well-defined sets of genes responsible for cell growth, cell fate determination, and cellular invasiveness. Differentially expressed genes of interest were confirmed using real-time RT-PCR. We found that TNF induced the expression of Notch-1, Notch-4, and Jagged-2 in RSF. The expression of these proteins was detected in the RA synovial tissues. The nucleus of RA synoviocytes showed strong staining with anti-Notch-1 and Notch-4 antibody. TNF induced the nuclear translocation of Notch intracellular domain in RSF, indicating the elicitation of the Notch signaling. Notch-1, Notch-4, and Jagged-2 proteins were also detected in the developing synovium of mouse embryo. Thus, RSF may have re-acquired the primordial phenotype, accounting for the hyperproliferation and aggressive invasiveness, exhibiting tumor-like phenotype.