NOTCH2 sensitizes the chondrocyte to the inflammatory response of tumor necrosis factor α.
NOTCH2 sensitizes the chondrocyte to the inflammatory response of tumor necrosis factor α.
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DOI：
10.1016/j.jbc.2023.105372
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发表时间：
2023-12
影响因子：
4.8
通讯作者：
Schilling, Lauren
中科院分区：
文献类型：
--
作者：
Canalis, Ernesto;Yu, Jungeun;Singh, Vijender;Mocarska, Magda;Schilling, Lauren
Notch调节免疫和炎症反应，并与人类骨关节炎的发病机制和疾病的临床前模型有关。can小鼠携带NOTCH2功能获得并对骨关节炎敏感，但其机制尚未探索。我们检测了肿瘤坏死因子α (TNFα)对Notch2tm1.1Ecan小鼠软骨细胞的影响，发现NOTCH2增强了TNFα对Il6和Il1b表达的影响。在NOTCH2功能获得的条件模型Notch22.1Ecan小鼠的细胞中，以及体外NOTCH2细胞内结构域的表达，也获得了类似的结果。免疫球蛋白Kappa J区重组信号结合蛋白与NOTCH2胞内结构域合作激活转录在缺乏Notch信号的情况下，它会抑制转录，软骨细胞中的Rbpj失活导致il - 6诱导。虽然TNFα在NOTCH2激活的情况下更大程度地诱导IL6，但Notch靶基因Hes1、Hey1、Hey2和Heyl同时受到抑制。电泳迁移位移分析显示，TNFα将免疫球蛋白Kappa J区的重组信号结合蛋白从DNA结合位点上置换，这解释了Il6表达增加和Notch靶基因的减少。NOTCH2增强了TNFα对NF-κB信号传导的作用，RNA-Seq显示，在TNFα缺失和存在的情况下，NOTCH2过表达细胞中炎症相关通路和吞噬体的表达增加。总的来说，NOTCH2与TNFα有重要的相互作用，导致软骨细胞中il - 6和炎症途径的表达增强。
Notch regulates the immune and inflammatory response and has been associated with the pathogenesis of osteoarthritis in humans and preclinical models of the disease. Notch2tm1.1Ecan mice harbor a NOTCH2 gain-of-function and are sensitized to osteoarthritis, but the mechanisms have not been explored. We examined the effects of tumor necrosis factor α (TNFα) in chondrocytes from Notch2tm1.1Ecan mice and found that NOTCH2 enhanced the effect of TNFα on Il6 and Il1b expression. Similar results were obtained in cells from a conditional model of NOTCH2 gain-of-function, Notch22.1Ecan mice, and following the expression of the NOTCH2 intracellular domain in vitro. Recombination signal-binding protein for immunoglobulin Kappa J region partners with the NOTCH2 intracellular domain to activate transcription; in the absence of Notch signaling it inhibits transcription, and Rbpj inactivation in chondrocytes resulted in Il6 induction. Although TNFα induced IL6 to a greater extent in the context of NOTCH2 activation, there was a concomitant inhibition of Notch target genes Hes1, Hey1, Hey2, and Heyl. Electrophoretic mobility shift assay demonstrated displacement of recombination signal-binding protein for immunoglobulin Kappa J region from DNA binding sites by TNFα explaining the increased Il6 expression and the concomitant decrease in Notch target genes. NOTCH2 enhanced the effect of TNFα on NF-κB signaling, and RNA-Seq revealed increased expression of pathways associated with inflammation and the phagosome in NOTCH2 overexpressing cells in the absence and presence of TNFα. Collectively, NOTCH2 has important interactions with TNFα resulting in the enhanced expression of Il6 and inflammatory pathways in chondrocytes.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
Hajdu-Cheney综合征患者Notch2突变。
影响因子：
4
作者：
Zhao, W.;Petit, E.;Gafni, R. I.;Collins, M. T.;Robey, P. G.;Seton, M.;Miller, K. K.;Mannstadt, M.
通讯作者：
Mannstadt, M.
巨噬细胞和骨炎症
影响因子：
6.6
作者：
Gu Q;Yang H;Shi Q
通讯作者：
Shi Q
影响因子：
9.8
作者：
Canalis, Ernesto
通讯作者：
Canalis, Ernesto
影响因子：
48
作者：
Gibson, Daniel G.;Young, Lei;Smith, Hamilton O.
通讯作者：
Smith, Hamilton O.