IKKε aggravates inflammatory response via activation of NF-κB in rheumatoid arthritis.
IKKε aggravates inflammatory response via activation of NF-κB in rheumatoid arthritis.
复制标题
IKKε 通过激活 NF-κB 加剧类风湿关节炎中的炎症反应。
DOI：
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发表时间：
2018
影响因子：
3.3
通讯作者：
G. Wu
中科院分区：
文献类型：
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作者：
L;W. Zeng;Lin Sun;Y. Wang;F. Jiang;X. Li;Y. Zheng;G. Wu
目的
类风湿性关节炎（RA）是一种慢性全身性自身免疫性疾病，其病因至今仍不清楚。RA的典型病理表现包括持续性滑膜炎和周围关节的骨变性。本研究旨在探讨IKKε（inhibitor of nuclear factor kappa-B kinase ε，核因子κ B激酶ε抑制剂）对Ⅱ型胶原诱导的类风湿性关节炎（CIA）小鼠模型的治疗作用及其主要机制。
材料和方法
IKKε-/-和野生型（WT）同窝对照小鼠腹腔注射5 mg/kg II型胶原单克隆抗体混合物（Cab）5天。观察小鼠痛阈和临床类风湿关节炎关节损伤评分。治疗5 d后，采用酶联免疫吸附法（ELISA）检测两组患者血清中白细胞介素6（IL-6）、IL-1β、肿瘤坏死因子-α（TNF-α）和干扰素（IFN）的水平。采用实时荧光定量逆转录聚合酶链反应（Real-time RT-PCR）检测各组大鼠足底组织中炎性细胞因子的表达。Western blot检测NF-κB（nuclear factor kappa-light-chain-enhancer of activated B）信号通路的蛋白水平。此外，接受CAb的WT小鼠进一步应用或不应用IKK抑制剂氨来昔单抗（25 mg/kg）以研究上述炎性细胞因子的表达。
结果
我们的工作表明，IKKε-/-小鼠与CIA表现出较低的伤害感受和抑制炎症反应比WT小鼠。同时，IKKε-/-小鼠的临床类风湿关节炎关节损伤评分显著降低。IKKε-/-小鼠血清和足底组织中TNF-α、IL-1β、IL-6水平均显著低于WT小鼠。IKKε-/-小鼠NF-κB表达明显降低。同样地，在给予IKKε抑制剂氨来萨诺的WT小鼠中观察到与IKKε-/-小鼠相同的表型，表明炎症和伤害感受反应比阴性对照显著降低。
结论
IKKε在CIA的伤害感受和炎症反应中起重要作用。我们的研究表明IKKε基因敲除可能为类风湿关节炎的临床防治提供新的方向。IKKε抑制剂氨来沙诺可能成为治疗类风湿关节炎的新药。
OBJECTIVE
Rheumatoid Arthritis (RA) is a chronic systemic autoimmune disease, whereas its cause still remains elusive. Typical pathological manifestations of RA include persistent synovitis and bone degeneration in the surrounding joints. Although the incidence of RA is high in population, currently there have been no effective cures for it. The purpose of this study is to investigate the therapeutic effects and main mechanism of IKKε (inhibitor of nuclear factor kappa-B kinase ε) in collagen II induced- Rheumatoid Arthritis (CIA) mice model.
MATERIALS AND METHODS
IKKε-/- and wild-type (WT) littermate control mice were intraperitoneally injected with 5 mg/kg collagen II monoclonal antibody cocktail (Cab) for 5 days. After that, the nociception threshold and clinical rheumatoid arthritis articular damage score of mice were evaluated. After 5 days-CAb treatment, serum levels of a series of inflammatory cytokines including interleukin-6 (IL-6), IL-1β, tumor necrosis factor-α (TNF-α) and interferon (IFN) were detected with enzyme-linked immunosorbent assay (ELISA) in both groups. Besides, Real-time reverse transcription polymerase chain reaction (Real-time RT-PCR) was used to evaluate the expression of these inflammatory cytokines in plantar tissues. In addition, Western blot was performed to investigate the protein levels of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B) signaling pathway. Moreover, WT mice receiving CAb were further applied with or without IKK inhibitor amlexanox (25 mg/kg) to investigate the expression of the above-mentioned inflammatory cytokines.
RESULTS
Our work showed that IKKε-/- mice with CIA displayed less nociception and suppressed inflammatory response than WT mice. Meanwhile, the clinical rheumatoid arthritis articular damage scores were significantly decreased in IKKε-/- mice. The levels of TNF-α, IL-1β, IL-6 in serum and plantar tissues in IKKε-/- mice were significantly lower than those in WT mice. Besides, NF-κB expression in IKKε-/- mice was significantly decreased. Similarly, the same phenotype was observed in WT mice administrated with IKKε inhibitor amlexanox as that of IKKε-/- mice, indicating that inflammatory and nociception responses were remarkably decreased than those of the negative controls.
CONCLUSIONS
IKKε plays an important role in promoting nociception and inflammatory response in CIA. Our research demonstrated that knockout of IKKε may serve as a new direction for clinical prevention and treatment of rheumatoid arthritis. IKKε inhibitor amlexanox may become a new drug for the treatment of rheumatoid arthritis.
影响因子：
2.3
作者：
Sparks, Jeffrey A.;Costenbader, Karen H.
通讯作者：
Costenbader, Karen H.