IL-6的发现及抗il - 6r抗体的研制

IF 1.1 Q4 MEDICINE, RESEARCH & EXPERIMENTAL
Tadamitsu Kishimoto
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引用次数: 7

摘要

我们对IL-6的一系列研究表明,它在多种组织和细胞中具有多效性,其不受调节的表达是多种慢性炎症和造血恶性肿瘤的原因。抗80kd IL-6R人源化抗体(Tocilizumab)在RA、JIA、Castleman’s病以及巨细胞动脉炎、反应性关节炎、风湿性多肌痛、成人still’s病等多种自身免疫性炎症疾病中显示出显著的治疗效果。CAR-T细胞疗法诱导的细胞因子风暴已被证明是由Tocilizumab控制的。托珠单抗的治疗效果证实了IL-6的过度和组成性产生与自身免疫性疾病的发病机制有关。那么,要问的问题是如何调节IL-6的产生。我们发现了一种名为Arid5a的新分子,它与IL-6 mRNA的3'-UTR结合,并通过与Regnase-1竞争来保护其降解。有趣的是,这种分子存在于细胞核中,炎症刺激诱导Arid5a从细胞核转位到细胞质中,并与regase -1竞争IL-6 mRNA的保护。我们的研究表明Arid5a是炎症和脓毒性休克发生的关键分子之一。该结果还提示Arid5a抗激动剂在预防各种炎症性疾病和感染性休克方面的治疗潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Discovery of IL-6 and Development of Anti-IL-6R Antibody.

A series of our studies on IL-6 have revealed that it has a pleiotropic activity in various tissues and cells and its deregulated expression is responsible for several chronic inflammations and hemopoietic malignancies.Humanized antibody against 80kd IL-6R (Tocilizumab) has shown significant therapeutic effect in RA, JIA, Castleman's diseases and several other autoimmune inflammatory diseases, such as, giant cell arteritis, reactive arthritis, polymyalgia rheumatica and adult still's disease. Cytokine storm induced by CAR-T cell therapy has been shown to be controlled by Tocilizumab.Therapeutic effect of Tocilizumab confirmed that over and constitutive-production of IL-6 is responsible for the pathogenesis of autoimmune diseases.Then, the question to be asked is how is IL-6 production regulated. We identified a novel molecule called Arid5a which binds with the 3'-UTR of IL-6 mRNA and protects its degradation by competing with Regnase-1. Interestingly, this molecule is present in nuclei and inflammatory stimulation induced translocation of Arid5a from nuclei into cytoplasm and it competes with Regnase-1 for the protection of mRNA of IL-6.Our study indicates that Arid5a is one of the key molecules for inflammation as well as the development of septic shock.The results also suggest the therapeutic potential of anti-agonistic agents for Arid5a in the prevention of various inflammatory diseases and septic shock.

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来源期刊
KEIO JOURNAL OF MEDICINE
KEIO JOURNAL OF MEDICINE MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
3.10
自引率
0.00%
发文量
23
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