Tumor necrosis factor α induces sustained signaling and a prolonged and unremitting inflammatory response in rheumatoid arthritis synovial fibroblasts.
Tumor necrosis factor α induces sustained signaling and a prolonged and unremitting inflammatory response in rheumatoid arthritis synovial fibroblasts.
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肿瘤坏死因子α诱导持续的信号传导，并在类风湿关节炎滑膜成纤维细胞中延长且不舒服的炎症反应。
DOI：
10.1002/art.37853
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发表时间：
2013-04
影响因子：
--
通讯作者：
Kalliolias GD
中科院分区：
文献类型：
--
作者：
Lee A;Qiao Y;Grigoriev G;Chen J;Park-Min KH;Park SH;Ivashkiv LB;Kalliolias GD
类风湿关节炎（RA）滑膜炎症的不溶解性是一个难题。为了确定成纤维细胞样滑膜细胞（FLS）对滑膜炎持续发展的贡献，我们研究了人类FLS中tnf α驱动炎症程序的分子机制。用TNFα刺激RA或骨关节炎患者滑膜组织的FLS，用qPCR和ELISA检测FLS的基因表达和细胞因子的产生。Western blotting检测NF-κB信号通路。通过染色质免疫沉淀和限制性内切酶可及性测定组蛋白乙酰化、染色质可及性、NF-κB p65和RNA聚合酶II （Pol II）在IL6启动子上的占用。在FLS中，TNFα诱导IL-6转录延长，IL-6蛋白在4天内逐渐积累。同样，TNFα刺激后CXCL8/IL-8、CCL5/RANTES、MMP1和MMP3 mRNA的诱导持续数天。这与巨噬细胞对TNFα的反应形成对比，后者的特征是促炎基因表达的短暂增加。在FLS中，TNFα诱导NF-κB信号的延长激活和持续的转录活性，表现为组蛋白乙酰化、染色质可及性以及il - 6启动子p65和Pol II占用的增加。此外，FLS表达低水平的终止巨噬细胞炎症反应的反馈抑制剂ABIN3、IRAK-M、SOCS3和ATF3。tnf - α信号在FLS中不能有效终止，导致不受控制的炎症反应。结果表明，FLS对滑膜TNFα的反应延长和持续的炎症反应有助于RA滑膜炎症的持续存在。
The non resolving character of synovial inflammation in rheumatoid arthritis (RA) is a conundrum. To identify the contribution of fibroblast-like synoviocytes (FLS) to the perpetuation of synovitis, we investigated the molecular mechanisms that govern the TNFα-driven inflammatory program in human FLS. FLS obtained from synovial tissues of patients with RA or osteoarthritis were stimulated with TNFα and assayed for gene expression and cytokine production by qPCR and ELISA. NF-κB signaling was evaluated using Western blotting. Histone acetylation, chromatin accessibility, and NF-κB p65 and RNA polymerase II (Pol II) occupancy at the IL6 promoter were measured by chromatin immunoprecipitation and restriction enzyme accessibility assays. In FLS, TNFα induced prolonged transcription of IL6 and progressive accumulation of IL-6 protein over four days. Similarly, induction of CXCL8/IL-8, CCL5/RANTES, MMP1 and MMP3 mRNA after TNFα stimulation was sustained for several days. This contrasted with the macrophage response to TNFα, which characteristically involved a transient increase in the expression of pro-inflammatory genes. In FLS, TNFα induced prolonged activation of NF-κB signaling and sustained transcriptional activity indicated by increased histone acetylation, chromatin accessibility, and p65 and Pol II occupancy at the IL6 promoter. Furthermore, FLS expressed low levels of the feedback inhibitors ABIN3, IRAK-M, SOCS3 and ATF3 that terminate inflammatory responses in macrophages. TNFα signaling is not effectively terminated in FLS, leading to an uncontrolled inflammatory response. The results suggest that prolonged and sustained inflammatory responses by FLS, in response to synovial TNFα, contribute to the persistence of synovial inflammation in RA.
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影响因子：
32.4
作者：
Kontoyiannis, D;Pasparakis, M;Kollias, G
通讯作者：
Kollias, G
DOI：
10.1084/jem.20070906
发表时间：
2008-02-18
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Armaka M;Apostolaki M;Jacques P;Kontoyiannis DL;Elewaut D;Kollias G
通讯作者：
Kollias G
影响因子：
--
作者：
García-Vicuña, R;Gómez-Gaviro, MV;Díaz-González, F
通讯作者：
Díaz-González, F
影响因子：
4.4
作者：
Devauchelle, Valerie;Essabbani, Abdellatif;Chiocchia, Gilles
通讯作者：
Chiocchia, Gilles
p21激活激酶1在调节类风湿性关节炎成纤维样滑膜细胞迁移和侵袭中的作用
影响因子：
5.5
作者：
Fu, Di;Yang, Yanlong;Xu, Hanshi
通讯作者：
Xu, Hanshi