Topical application with a new NF-κB inhibitor improves atopic dermatitis in NC/NgaTnd mice
Topical application with a new NF-κB inhibitor improves atopic dermatitis in NC/NgaTnd mice
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DOI：
10.1038/sj.jid.5700603
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发表时间：
2007-04-01
影响因子：
6.5
通讯作者：
Matsuda, Hiroshi
中科院分区：
文献类型：
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作者：
Tanaka, Akane;Muto, Susumu;Matsuda, Hiroshi
越来越多的证据表明NF-κ B B活化在变应性疾病中对疾病严重程度的重要作用。在这项研究中，我们研究了一种新的NF-κ B B抑制剂IMD-0354的临床相关性，特应性皮炎（AD）的局部应用。为了研究体内功效，每天将1%IMD-0354软膏施用于具有严重皮炎的NC/NgaTnd小鼠，其用作人AD的模型。在2周给药期间，IMD-0354和FK 506给药小鼠的抓挠行为减少，皮炎严重程度降低，无不同影响。基于组织学检查，在IMD-0354处理的小鼠的皮肤中，角质形成细胞的增生和炎性细胞的浸润显著减少。在IMD-0354处理的小鼠中，受影响皮肤部位的T辅助细胞2细胞因子和肿瘤坏死因子-α的表达下调。此外，IMD-0354抑制各种免疫活性细胞的增殖、神经生长因子刺激的嗜铬细胞瘤细胞的神经突生长、脾B细胞的IgE产生和IgE介导的肥大细胞体外活化。IMD-0354有效地减少了NC/NgaTnd小鼠体内的过敏性炎症。因此，干扰NF-κ B活性的药物可能为治疗AD提供替代治疗策略。
Growing evidence has demonstrated the crucial role of NF-kappa B activation on disease severity in allergic disorders. In this study, we examined the clinical relevance of a novel NF-kappa B inhibitor, IMD-0354, for atopic dermatitis (AD) by its topical application. To investigate the in vivo efficacy, 1% IMD-0354 ointment was applied daily to NC/NgaTnd mice with severe dermatitis, which served as a model for human AD. During 2 weeks of treatment, scratching behavior decreased and severity of dermatitis reduced in mice treated with IMD-0354 as well as FK506 without diverse effects. Based on histological examinations, the hyperplasia of keratinocytes and infiltration of inflammatory cells were significantly reduced in the skin of IMD-0354-treated mice. The expressions of T-helper 2 cytokines and tumor necrosis factor-alpha at the affected skin sites were down-regulated in IMD-0354-treated mice. Furthermore, IMD-0354 suppressed the proliferation of various immunocompetent cells, neurite outgrowth of nerve growth factor-stimulated pheochromocytoma cells, IgE production from splenic B cells, and IgE-mediated activation of mast cells in vitro. IMD-0354 effectively reduced the allergic inflammation in NC/NgaTnd mice in vivo. Thus, a drug that interferes with NF-kappa B activity may provide an alternative therapeutic strategy for the treatment of AD.