Effect of a small molecule inhibitor of nuclear factor-kappaB nuclear translocation in a murine model of arthritis and cultured human synovial cells.
Effect of a small molecule inhibitor of nuclear factor-kappaB nuclear translocation in a murine model of arthritis and cultured human synovial cells.
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DOI：
10.1186/ar1834
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发表时间：
2005
影响因子：
4.9
通讯作者：
Kubota T
中科院分区：
文献类型：
--
作者：
Wakamatsu K;Nanki T;Miyasaka N;Umezawa K;Kubota T
小细胞渗透性化合物脱羟甲基表氧喹诺霉素（DHMEQ）不抑制IκB（核因子-κB [NF-κB]抑制剂）的磷酸化和降解，但选择性抑制活化NF-κB的核转位。本研究旨在证明这种新型NF-κB通路抑制剂在小鼠关节炎模型体内和体外人滑膜细胞中的抗关节炎作用。在小鼠中诱导胶原诱导的关节炎，并且在关节炎发作后，用DHMEQ（每天5 mg/kg体重）治疗小鼠。采用电泳迁移率变动法检测类风湿关节炎（RA）患者滑膜成纤维样细胞（FLS）中NF-κB活性。采用RT-PCR、ELISA和流式细胞术检测RA发病机制相关分子的表达。用氚标记胸苷掺入法测定细胞增殖活性。在用DHMEQ处理14天后，与仅用载体处理的对照小鼠相比，基于爪肿胀程度、肿胀关节的数量以及放射学和组织病理学评分，患有胶原诱导的关节炎的小鼠表现出关节炎严重程度降低。在用肿瘤坏死因子-α刺激的RA FLS中，DHMEQ抑制NF-κB组分p65和p50的活性，导致抑制关键炎性细胞因子IL-6、CC趋化因子配体-2和-5、基质金属蛋白酶-3、细胞间粘附分子-1和血管细胞粘附分子-1的表达。细胞的增殖活性也受到抑制。这是第一次证明NF-κB核转位抑制剂对已建立的小鼠关节炎具有治疗作用，抑制FLS中的炎症介质被认为是这种作用的机制之一。
A small cell-permeable compound, dehydroxymethylepoxyquinomicin (DHMEQ), does not inhibit phosphorylation and degradation of IκB (inhibitor of nuclear factor-κB [NF-κB]) but selectively inhibits nuclear translocation of activated NF-κB. This study aimed to demonstrate the antiarthritic effect of this novel inhibitor of the NF-κB pathway in vivo in a murine arthritis model and in vitro in human synovial cells. Collagen-induced arthritis was induced in mice, and after onset of arthritis the mice were treated with DHMEQ (5 mg/kg body weight per day). Using fibroblast-like synoviocyte (FLS) cell lines established from patients with rheumatoid arthritis (RA), NF-κB activity was examined by electrophoretic mobility shift assays. The expression of molecules involved in RA pathogenesis was determined by RT-PCR, ELISA, and flow cytometry. The proliferative activity of the cells was estimated with tritiated thymidine incorporation. After 14 days of treatment with DHMEQ, mice with collagen-induced arthritis exhibited decreased severity of arthritis, based on the degree of paw swelling, the number of swollen joints, and radiographic and histopathologic scores, compared with the control mice treated with vehicle alone. In RA FLS stimulated with tumor necrosis factor-α, activities of NF-κB components p65 and p50 were inhibited by DHMEQ, leading to suppressed expression of the key inflammatory cytokine IL-6, CC chemokine ligand-2 and -5, matrix metalloproteinase-3, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1. The proliferative activity of the cells was also suppressed. This is the first demonstration of an inhibitor of NF-κB nuclear translocation exhibiting a therapeutic effect on established murine arthritis, and suppression of inflammatory mediators in FLS was thought to be among the mechanisms underlying such an effect.
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影响因子：
15.3
作者：
Gong, JH;Ratkay, LG;Waterfield, JD;ClarkLewis, I
通讯作者：
ClarkLewis, I
通过全身施用膜可渗透的Ikappabalpha抑制剂，炎症部位的浸润减少和白细胞凋亡增加。
影响因子：
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作者：
Blackwell, Nathan M;Sembi, Phupinder;Newson, Justine S;Lawrence, Toby;Gilroy, Derek W;Kabouridis, Panagiotis S
通讯作者：
Kabouridis, Panagiotis S
影响因子：
56.9
作者：
KOPP, E;GHOSH, S
通讯作者：
GHOSH, S
影响因子：
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作者：
di Meglio, Paola;Ianaro, Angela;Ghosh, Sankar
通讯作者：
Ghosh, Sankar
影响因子：
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作者：
Andreakos, E;Smith, C;Foxwell, BM
通讯作者：
Foxwell, BM